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Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study

Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after... Journal of Neuroimmunology 391 (2024) 578363 Contents lists available at ScienceDirect Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim Endothelial dysfunction in neurodegenerative disease: Is endothelial inflammation an overlooked druggable target? Megan Ritson , Caroline P.D. Wheeler-Jones , Helen B. Stolp Department of Comparative Biomedical Sciences, Royal Veterinary College, London NW1 0TU, UK ARTICLE INFO ABSTRACT Keywords: Neurological diseases with a neurodegenerative component have been associated with alterations in the cere- Neurodegeneration brovasculature. At the anatomical level, these are centred around changes in cerebral blood flow and vessel Endothelium organisation. At the molecular level, there is extensive expression of cellular adhesion molecules and increased Blood-brain barrier release of pro-inflammatory mediators. Together, these has been found to negatively impact blood-brain barrier Inflammation integrity. Systemic inflammation has been found to accelerate and exacerbate endothelial dysfunction, neuro - Cerebrovascular inflammation and degeneration. Here, we review the role of cerebrovasculature dysfunction in neurodegener - ative disease and discuss the potential contribution of intermittent pro-inflammatory systemic disease in causing endothelial pathology, highlighting a possible mechanism that may allow broad-spectrum therapeutic targeting in the future. 1. Neurodegeneration and the cerebrovasculature neurodegenerative disorders via several processes (reviewed by Ware- ham et al., 2022), and have been suggested to play a critical role in the The prevalence of neurological disease with a neurodegenerative aetiology of these conditions (Drouin-Ouellet et al., 2015; Hatate et al., component is rapidly increasing due to the aging global population 2016). More work is required to definitively support this link, which is (Wyss-Coray, 2016). This collection of primarily sporadic diseases partly strengthened by the increasing evidence that vascular dysfunction affecting the central nervous system (CNS) are often characterised by is an early part of disease pathophysiology (Kelleher and Soiza, 2013; ´ ´ neurodegeneration of neuronal populations or axonal processes, across a Apatiga-Perez et al., 2022; Yuan et al., 2023). If true, a renewed focus on lifespan (Heemels, 2016). The most common examples include Alz- the cerebrovascular contribution to NDDs may add to our understanding heimer’s disease (AD), Parkinson’s disease (PD) and Multiple Sclerosis of disease aetiology and treatment options. As the interface between the (MS) (DeTure and Dickson, 2019; Simon et al., 2020; Mey et al., 2023). brain and the rest of the body, the endothelial cells (ECs) that make up In addition, secondary neurodegeneration can arise following a large the cerebrovasculature are exposed to a plethora of minor (and major) vascular injury such stroke (Ong, 2022). Neurological diseases with a insults across a lifetime that may alter their function and disrupt the substantial degenerative component (from here on termed neurode- neuronal cells they protect. Equally, the ECs of the blood-brain barrier generative diseases, NDDs), are diverse in presentation and pathology, (BBB), unlike the neuronal cells beyond this barrier, are a highly drug- causing an array of life altering symptoms including memory impair- gable target and therefore may represent a future theragnostic target, ment, cognitive deficits, loss of motor function and respiratory compli - exploitable both as a diagnostic biomarker and for a disease modifying cations (Erkkinen et al., 2018). Treatment options for these conditions treatment. are primarily limited to symptom management (Wareham et al., 2022). In this broad review, we discuss the role of ECs in regulating cere- New therapies directly targeting disease processes have recently been brovascular function, summarise the evidence for cerebrovascular identified for AD, though it remains unclear how efficacious these will dysfunction in NDDs and suggest mechanisms by which ECs may be in clinical practice given limitations of diagnostic capacity (Larkin, contribute to this. We also make a link between systemic disease and 2023; van Dyck et al., 2023). There is, therefore, a pressing need for endothelial injury, a mechanism through which repeated peripheral novel therapeutic approaches. inflammation may contribute to NDD severity and progression that Alterations within the cerebral microvasculature may contribute to could be exploited in the future to diagnose and treat patients. * Corresponding author at: Department of Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London NW1 0TU, UK. E-mail address: [email protected] (H.B. Stolp). https://doi.org/10.1016/j.jneuroim.2024.578363 Received 21 December 2023; Received in revised form 29 March 2024; Accepted 2 May 2024 Available online 3 May 2024 0165-5728/© 2024 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). M. Ritson et al. Journal of Neuroimmunology 391 (2024) 578363 2. The endothelium, blood-brain barrier, and neurovascular periphery (Andreone et al., 2017) and have a high presence of efflux unit transporters which restrict access of specific lipophilic molecules to the brain (Qosa et al., 2015). As a counter to this restrictive barrier, brain The endothelium, a monolayer of ECs, lines the luminal surface of all ECs express multiple transporters to support the active movement of blood vessels within the body, forming the critical interface between the specific solutes in and out of the brain and consequently have a high blood and the tissue, and orchestrating vascular function. ECs have a mitochondrial density (Kadry et al., 2020). Together, these specialisa- heterogeneity of structure and function which has been described at the tions allow the ECs of the BBB to protect the CNS from fluctuations in the morphological, functional, and genomic levels (Aird, 2012; Jambusaria systemic environment (Lansdell et al., 2022), and disruption in these et al., 2020). Signals from within the tissue microenvironment, such as mechanisms are hallmarks of neurodegenerative conditions. those generated through cell-cell interactions, together with release of While there are many factors that may lead, at a cellular level, to growth factors, can influence tissue-specific adaptations of ECs (Potente altered vascular function or disruption of the BBB, this review focuses on and Makinen, 2017), enabling them to perform various physiological inflammation as a process with important commonality to systemic roles in tissues including the modulation of vascular tone, platelet ag- disease and NDDs. Many systemic conditions that are associated with gregation, angiogenesis, leukocyte trafficking and other responses to vascular injury in the periphery, such as diabetes and high serum inflammation (Ait-Oufella et al., 2010; Sturtzel, 2017). cholesterol, result in increased circulating inflammatory mediators that In terms of their contribution to vascular tone, and therefore regional will inevitably interact with the cerebral ECs (Que et al., 2018; Sheikh blood flow, healthy ECs produce multiple vasoactive mediators that act et al., 2022). When sufficiently severe, systemic inflammation results in on surrounding contractile cells to either constrict or dilate the blood acute, transient inflammation of the cerebral endothelium (Verma et al., vessels (see Sandoo et al., 2010 for a review on the molecular regulation 2006) and altered function of the cerebrovasculature and the BBB of these processes). Many of these actions typically occur in arterioles (Sheikh et al., 2022; Banks et al., 2015). Normal aging and neuro- and post-capillary venules through modulation of smooth muscle cell degeneration also cause inflammation of systemic and cerebrovascular function, regulating blood flow at a mesoscale, and are common across ECs (see Finger et al., 2022), and acute systemic inflammation can vascular beds. In the cerebrovasculature, there is additional regulation reactivate dormant neuroinflammatory lesions (Serres et al., 2009) and of blood flow via neurovascular coupling at the level of the capillary affect amyloid clearance from the brain (Erickson et al., 2012), sug- which is utilised to regulate and maintain regional cerebral blood flow gesting a complex interplay between (systemic) inflammation and (CBF) in response to local activity (Otsu et al., 2015; Iadecola, 2017; neurological injury. Ahmad et al., 2020; Stackhouse and Mishra, 2021). The vascular endothelium is a key modulator of the acute inflam - Within the neurovascular unit (NVU; Fig. 1), the ECs are specialised matory response, promoted by abnormal physiological stimuli, damage, compared to those in most peripheral vascular beds and form the BBB, or infection (Leick et al., 2014). A recent analysis of peripheral and the regulated interface between the peripheral circulation and the CNS cerebral endothelial inflammatory responses suggests that a subset of (Macdonald et al., 2010; Koizumi et al., 2016). ECs exhibit continuous ECs may even have a specific immunomodulatory role (Amersfoort junctions between adjacent cells, sealed by tight junction complexes, et al., 2022), possibly contributing to immune surveillance as well as which are important for creating a functional anatomical barrier into the tissue pathology. During acute inflammation, there is increased release brain (Liu et al., 2012). There is a substantial body of work on the nature of pro-inflammatory cytokines and upregulation of cellular adhesion of these junctions (for a recent review see Lochhead et al., 2020), with molecule (CAM) expression. These processes occur in all vascular beds, the presence and structural organisation of claudin and occludin pro- the underlying molecular mechanisms at the BBB have been well teins considered particularly essential for junctional integrity. ECs described (Dietrich, 2002; Müller, 2019; Wimmer et al., 2019). within the CNS also demonstrate low rates of vesicle transport, due to Numerous transcriptomics studies in rodent models of acute systemic the inhibition of caveolae-mediated transcytosis regularly utilised in the inflammation have added to our understanding of the early (Kodali et al., 2020; Struck et al., 2024) and later stages (Munji et al., 2019) of endothelial inflammatory signalling. These studies show that at base - line, genes associated with chemokine signalling, antigen presentation and leukocyte diapedesis (e.g. ICAM-1, VCAM-1, CCL2) are more highly expressed in peripheral vessels compared to cerebral ECs (Munji et al., 2019). Cerebral ECs up-regulate pathways associated with nuclear fac- tor- kappa B (NF-κB) signalling within 15 min of a peripheral inflam - matory stimulus followed, at later time points, by genes governing cytokine and chemokine production and leukocyte migration (Kodali et al., 2020), similar to changes observed in peripherally derived ECs (Struck et al., 2024). Overall, current evidence implied that cerebral ECs appear adopt a phenotype comparable to that of peripheral ECs following systemic challenge, with down regulation of BBB-enriched genes and increases in inflammatory genes (Munji et al., 2019). It should be noted that the majority of studies in models of vascular inflammation utilise high concentrations of lipopolysaccharide (LPS) or TNF. As a result, the timing, magnitude and composition of the endo- thelial inflammatory response would likely vary in more disease specific injury models or in patient responses. Generally, the acute inflammatory response is confined and benefi - cial, providing protection from pathogenic stimuli, particularly in the periphery. However, if inefficient resolution occurs, detrimental chronic Fig. 1. The Neurovascular Unit. inflammation can develop. At the microvascular level, endothelial Schematic illustration of the neurovascular unit (NVU) at the microvascular dysfunction is evident, characterised by a prolonged increased in the level. The NVU is comprised of endothelial cells, the basal lamina, pericytes, release of pro-inflammatory cytokines, impaired production of vasodi - astrocyte endfeet, neurones and microglia. These different components work lators, increased generation of vasoconstrictor molecules as well as together to maintain homeostasis of the brain microenvironment (Adapted from Dubois et al., 2014). upregulated expression of CAMs (Steyers and Miller Jr, 2014; Bennett 2 M. Ritson et al. Journal of Neuroimmunology 391 (2024) 578363 et al., 2018). In the periphery these changes have been well-described as The data from patients with neurodegenerative disease, as well as contributing to increased vasoconstriction and to enhanced leukocyte animal and cell models of these diseases is currently fragmentary (dis- migration, capillary permeability, and platelet aggregation (Pober and cussed in detail below). In order to reduce endothelial dysfunction in Sessa, 2007). Combined, these altered functions are responsible for the neurodegenerative diseases, it is important to understand and determine extensive damage exhibited in chronic inflammatory diseases in the how and when processes of endothelial dysfunction occur, whether the periphery such as atherosclerosis and rheumatoid arthritis (Murdaca common inflammatory pathways are activated equally in each condi - et al., 2012; Nikpour et al., 2013; Steyers and Miller Jr, 2014). tion, and if early-life injuries or systemic disease may alter the timing or Leukocyte transmigration, following increases in cytokine signalling magnitude of the cerebral endothelial response. This knowledge can be and upregulation of CAMs, is recognised to occur in the brain and used to identify early markers of the disease process and to investigate contributes to neurological disease, particularly in MS and stroke vascular targeted therapies as disease modifying agents. Therapeutic (Juurlink, 1998; Schmitt et al., 2012; Sienel et al., 2022; Fig. 2). While agents are already available that could be used to counter the detri- these pathways are not as active in physiological or low-inflammatory mental effects of a range of inflammatory mediators e.g. TNF (Chou states as in the periphery, leading to the original hypothesis of et al., 2016) and IFNGR1 (YetkIn and Gültekin, 2020), if stronger evi- immune-privilege in the brain, they can be substantially upregulated in dence for their involvement in the disease process merges. the brain under pathological conditions (recently reviewed in detail in Ludewig et al., 2019). The signalling pathways regulating trans- 3. Evidence for and against altered cerebral blood flow in migration, and the downstream consequences of this for cerebrovascular cerebrovascular and neurodegenerative diseases and parenchymal damage have been extensively reviewed elsewhere (Man et al., 2007; Larochelle et al., 2011; Takeshita and Ransohoff, In the absence of accessible and effective methods for measuring 2012). CBF, many studies investigating vascular dysfunction in neurodegener- The structural and functional alterations in the cerebral endothelium ative disease have focused on measuring peripheral endothelial function have been shown to lead to increased inflammation and oxidative stress, using flow-mediated dilation (FMD), a non-invasive ultrasonography which together severely impair neurovascular function (Lehner et al., technique that measures endothelium-dependent relaxation of the 2011; Liu et al., 2012). Dysfunction of the BBB is characterised by the brachial artery following reactive hyperemia. The difference in diameter loss of tight junction integrity, increased permeability, upregulated in the brachial artery compared to the basal diameter is considered to be transcytosis and increased CAM expression leading to an influx of in - the FMD, with an FMD value <7.8% being the cut-off for the diagnosis of flammatory mediators into the brain (Daneman, 2012; Koizumi et al., endothelial dysfunction (Korkmaz and Onalan, 2008; Mucka et al., 2016). 2022). In PD, FMD has been found to be significantly lower in patients Fig. 2. Mechanisms of endothelial inflammation in NDDs. Multiple mechanisms of endothelial inflammation have been confirmed to be present in different NDDs. Pro-inflammatory cytokines (e.g. TNF, IL-6) bind to their corresponding receptors on the endothelial cell surface (Aref et al., 2020; Magliozzi et al., 2021), shown to lead to the activation and translocation of NF-κB to the nucleus. As a consequence, this initiates transcription of genes hypothesised to be involved in the downstream functional changes arising from endothelial cell inflammation (Srinivasan et al., 2017; Zhou et al., 2023). The activation of the NF-κB pathway can also lead to the upregulation in the expression of cellular adhesion molecules (CAMs) such as ICAM-1 (Frohman et al., 1991; Lindsberg et al., 1996). Upregulation of CAMs facilitates the transmigration of leukocytes into the tissues (Brock et al., 2015; Quan et al., 2019), alongside the release of pro-inflammatory mediators (Grammas and Ovase, 2001). Additionally, inflammatory expression of von-Willibrand factor (vWF) mediates platelet activation and aggregation within the vessel (Mari et al., 1996; Sevush et al., 1998; Morel et al., 2015). The release of reactive oxygen species (ROS) occurs due to the uncoupling of endothelial nitric oxide synthase (eNOS), consequently leading to a decrease in nitric oxide (NO) and a state of oxidative stress (Szolnoki et al., 2005; Tan et al., 2015). 3 M. Ritson et al. Journal of Neuroimmunology 391 (2024) 578363 compared to age matched control subjects (7.1% compared to 8.1% in the brain after stroke, there is substantial evidence of systemic respectively) (Yoon et al., 2015). A small case-control study found AD vascular dysfunction contributing to the risk of stroke. Specifically, patients free of vascular risk factors to have lower FMD values than those atherosclerotic vascular changes (Libby et al., 2019), are a well- of control patients (3.45% compared to 8.41%, respectively) (Dede established risk factor for (non-cardioembolic) ischemic stroke, with et al., 2007). Disease severity, in particular lower scoring on cognitive ~70% of patients showing a substantial aortic plaque burden, and ~ tests, has also been reported to correlate with the decreased FMD values 20% having severe internal carotid artery stenosis (Serena et al., 2015). found in AD patients (Dede et al., 2007; Tachibana et al., 2016). Overall, The combination of high body mass and diabetes (both risk factors for these findings suggest that peripheral endothelial dysfunction, assessed atherosclerosis), as well as the presence of symptomatic peripheral ar- by FMD, is associated with multiple risk factors of AD. tery disease and intracranial artery stenosis, have all been identified as With respect to the brain, the obvious limitation of FMD is that it is a common risk factors for further stroke events occurring within a 12- measurement of peripheral endothelial dysfunction, and does not month period (Serena et al., 2015). directly indicate CBF or indeed other regional changes in brain blood While atherosclerosis is a systemic condition, and in part contributes flow associated with disease states. Technological advances in arterial to stroke risk by increasing the chance of a thrombotic event, the data spin labelling magnetic resonance imaging (ASL-MRI) have allowed the overall suggest that there may also be early changes occurring within the detection of a posterior hypoperfusion condition in PD patients within cerebral vascular beds that increase the risk of an ischemic occlusion. the parietooccipital cortex and posterior cingulate cortex (Kamagata This idea is supported by data from a meta-analysis that followed stroke et al., 2011; Arslan et al., 2020). A broader pattern of altered blood flow free individuals over a 5–12 year period, assessing the retinal vessels as has been reported by others (Wei et al., 2016), although not specifically biomarkers for stroke risk. Altered vessel calibre, specifically increased within the substantia nigra. These studies have shown that regional venular calibre was shown to be an independent risk factor for stroke hypoperfusion occurs in cognitively normal PD patients, and the degree (McGeechan et al., 2009). As many of the factors that contribute to of hypoperfusion is strongly correlated with mild cognitive impairment atherosclerosis also affect local vessel function (e.g., inflammatory cy - or dementia in addition to the PD diagnosis (Kamagata et al., 2011; tokines, increased ROS, enhanced leukocyte and platelet adhesion, Arslan et al., 2020). reduced nitric oxide production; Roquer et al., 2009), it is possible that Regional changes in CBF have also been measured using ASL-MRI in while atherosclerotic burden can increase the risk of stroke, much of this AD patients, with a recent meta-analysis indicating that reductions in risk arises directly from altered reactivity within the cerebrovascular blood-flow occur with normal aging and are exacerbated in AD, though beds. Current preventative treatments for cerebral small vessel disease with high variability in the affected brain regions reported between and their sequalae are largely focused on reducing risk factors, such as studies (Graff et al., 2023; Swinford et al., 2023). Altered regional CBF clot formation and reducing cholesterol (Smith and Markus, 2020). The has also been demonstrated using neuroimaging in patients following assessment of retinal vessel calibre provides proof-of-principle that stroke (Nakaoku et al., 2018), or who have been diagnosed with MS assessing vascular structure can provide insights into disease risk and - could lead to identification of more focused biomarkers related to (Zhang et al., 2018). However, it is difficult to make definitive state ments as to the location and magnitude of these changes given the vascular function, probably as part of a multi-tiered screening for early variation in presentation and evolution of these conditions compared to diagnosis and preventative therapy. In line with this aim, trials of allo- those studies conducted in PD and AD patients. purinol and cilostazol are currently being performed in patients with In AD, there has been a greater depth of research into the nature of cerebral small vessel disease to reduce endothelial inflammation and vascular disruption leading to altered regional CBF (reviewed by Korte increase the capacity to regulate vascular tone (reviewed in Smith and et al., 2020). There is clear evidence that damage to the capillaries can Markus, 2020). A similar change in therapeutic approach may be useful occur as a secondary response to amyloid deposition in AD patients in AD, where research utilising vessel size imaging to quantify vessel (Kimura et al., 1991), and cerebral amyloid angiopathy (CAA), the structure in an AD mouse model found decreased density and abnormal deposition of amyloid beta (Aβ) plaques on the walls of both brain ar- morphological changes in the microvessels at both early and late stages terioles and capillaries, is present in 90% of AD cases (Grinberg and of disease (Xu et al., 2020). Thal, 2010). This Aβ deposition can directly reduce CBF in both ex vivo Substantial disruption of BBB integrity is evident in most neurode- and in vivo AD models (Suo et al., 1998; Dietrich et al., 2010) by evoking generative disorders and commonly results in increased leakage of vasoconstriction through increased reactive oxygen species (ROS) pro- serum proteins into the brain. In PD patients, post-mortem analysis or in duction by the cerebral arteries (Niwa et al., 2001). In turn, this vivo MRI have specifically shown altered BBB permeability in the reduction in CBF increases the production of Aβ in vivo, forming a striatum and substantial nigra (Gray and Woulfe, 2015; Al-Bachari et al., damaging feedback loop (Sun et al., 2006; Zhang et al., 2007). At the 2020). A recent study has reported increased BBB leakage in a PD mouse capillary level, Aβ acts at pericyte-dense locations to cause constriction model with global overexpression of human alpha-synuclein (α-syn), a (in both human AD and mouse models) via a mechanism involving NOX- key protein involved in PD pathology (Gomez-Benito et al., 2020; Elabi 4-dependent reactive oxygen species (ROS) production and downstream et al., 2021). This was accompanied by localisation of α-syn within ECs, release of endothelin-1 (Nortley et al., 2019). The molecular and cellular inappropriate pericyte activation, and dynamic alterations in vessel mechanisms responsible for the reduced CBF in other NDDs remain to be density starting relatively early in the aging process (Elabi et al., 2021). determined. Interestingly, the authors showed increased vessel density at 8-months and decreased density at 13-months, potentially explained by an 4. Evidence for structural reorganisation of the initial increase in compensatory angiogenesis in the early stages of disease followed by vascular regression in the later stages (Elabi et al., cerebrovasculature and blood-brain barrier in 2021). These observations clearly place alterations in the cere- neurodegenerative disorders brovasculature as an early part of PD disease pathophysiology. The use of advanced neuroimaging in both human AD patients and Altered CBF in a pathological scenario may result from changes in vascular wall structure, affecting the compliance to modulatory signals AD animal models has identified breakdown of the BBB in early disease states (van de Haar et al., 2016; Alkhalifa et al., 2023). Deposition of Aβ from the endothelium. It is likely that these pathological alterations in tissue structure, along with associated modifications in local endothelial plaques has been directly associated with an increase in BBB perme- ability (Roher et al., 2003; Carrano et al., 2011; Zenaro et al., 2017). signalling, contribute to the measured changes in regional CBF discussed above. Similarly, in a rat BBB in vitro model, treatment with human tau increased endothelial permeability (Kovac et al., 2009). Decreases in The clearest data in this area come from investigations into the initiating factors of stroke. In addition to vascular disruption occurring both claudin-5 and occludin expression have been found in post-mortem 4 M. Ritson et al. Journal of Neuroimmunology 391 (2024) 578363 analyses of AD patient brains and are associated with increased Microvessels isolated from the brains of AD patients also show high permeability of the BBB (Yamazaki et al., 2019). In addition, a single levels of pro-inflammatory cytokines (Grammas & Ovase), and histo- intravenous injection of claudin-5 produced acute improvements in both logical studies in tissue from AD patients have reported elevated ICAM-1 learning and memory in the APP/PS1 mouse when assessed 1–4 days (reviewed in Grammas, 2011). post treatment (Zhu et al., 2022). While vascular inflammation is evident in these conditions, the onset BBB disruption has been recognised as a key component of MS and extent of inflammation in the aetiology of neurodegeneration re - pathophysiology (Claudio et al., 1995; Werring et al., 2000; Vos et al., mains a point of discussion. While many of the findings described above 2005a, 2005b; Cramer et al., 2015), typically considered a consequence reflect the response to cerebral injury and degeneration, there is also of the high level of leukocyte diapedeses. Investigations using gadolin- evidence of vascular inflammation indirectly contributing to the disease ium (Gd)-MRI to assess MS lesions recognised intense focal disruptions process and driving neuronal damage. Data in support of this are within the BBB, primarily centred around sites of extensive neuro- accumulating from studies on AD and stroke. In particular, cerebral ECs inflammation (Grossman et al., 1986; Miller et al., 1998). A study using isolated from AD patients have been reported to release toxic factors, dynamic-contrast MRI revealed a correlation between BBB disruption causing neuronal injury (Kelleher and Soiza, 2013), although the iden- and the appearance of MS lesions with disease relapse (Cramer et al., tity of these factors is yet to be confirmed. In vitro studies using micro- 2013). Gd-enhancing MRI techniques have also documented BBB vessels from AD patients showed that vascular-mediated neuronal death breakdown in the normal white matter as well as white matter lesions in occurred when naïve neurons were cultured directly with AD micro- MS patients (Lund et al., 2013; Choi et al., 2021), indicating a broader vessels, or with their conditioned media (Grammas, 2000). Additional in cerebrovascular dysfunction in this condition than the acute inflam - vitro work investigating pro-inflammatory cytokine-mediated activation matory lesions might suggest. Consistent with these MRI studies, post- of cerebral ECs has also demonstrated the release of neuron-toxic factors mortem histology has shown a decrease in the expression of the tight from ECs, leading to death of cholinergic neurons. These studies indicate junction proteins occludin and ZO-1 in the microvessels within active a role for the cerebral vasculature in contributing to the degeneration of MS lesions. Abnormalities in the structure of these tight junctions were cholinergic neurons observed in AD (Moser et al., 2006). These in vitro identified in ~40% of the vessels, including in white matter with a approaches suggest a direct role for the endothelium in the neuronal normal appearance (Plumb et al., 2002; Kirk et al., 2003). Tight junction death that underpins NDD aetiology. There is research in animal models abnormalities are associated with an increased leak of serum fibrinogen that have investigated the effects of systemic inflammation on the ce - within MS lesions (Vos et al., 2005a, 2005b; McQuaid et al., 2009). It has rebral vasculature, as discussed below (Marottoli et al., 2017), or the been suggested that increased entry of mediators such as fibrinogen into contribution of inflammation to neurodegeneration (Kitazawa et al., the CNS, resulting from continuously increased BBB permeability, can 2005; Catorce and Gevorkian, 2016; Huang et al., 2024). However, lead to the progressive demyelination characterising MS pathology, and further research into the involvement of early life vascular inflammation exacerbates neuroinflammation (Kirk et al., 2003). While there is clear and its link to neurodegenerative disease in later life is now warranted. evidence of loss of tight junction proteins in MS, a longitudinal case- control study of tight junction proteins in the blood of MS patients 6. Does altering endothelial cell or vascular function affect showed increased circulating levels of these proteins, but there was no neurodegenerative disease outcomes? clear correlation with MS disease severity (Olsson et al., 2021), limiting their potential use as diagnostic biomarkers in this condition. There is, To date, improvements in vascular function in NDDs have been therefore, need of further work in this, as in other neurodegenerative assessed following treatment of the non-vascular related elements of the conditions, to identify biomarkers of disease that can facilitate diagnosis disease process, thereby reducing the secondary vascular injury that and monitoring of disease progression and treatment. A more detailed occurs following neurodegeneration. For instance, a study using a mouse understanding of vascular injury may provide candidates for these new model of AD showed preservation of BBB integrity when tau is sup- biomarkers. pressed (Blair et al., 2015). Similarly, in an in vitro study using human brain ECs Aβ was shown to influence the integrity of the BBB primarily 5. Evidence for inflammatory injury as a driver of endothelial through the disruption of tight junction proteins such as claudin-5 cell dysfunction in neurodegenerative disorders (Griffin et al., 2016). Current therapies targeting the Aβ-induced neuropathology such as Lecanemab (an immunotherapy, targeting Aβ to In common with BBB breakdown, neuroinflammation has been slow AD progression; van Dyck et al., 2023) may therefore be effective identified in the cerebrovasculature in all the NDD conditions discussed, both through reducing primary disease and limiting exacerbation that though the body of evidence is greater in some than others. In MS, would otherwise follow amyloid-induced alterations in BBB integrity. A increased expression of CAMs and the associated leukocyte diapedesis question remaining, is whether therapies aimed at directly reducing BBB are well recognised. This is due in part to the presence of high levels of breakdown or other early stages of endothelial dysfunction, could ICAM-1 and VCAM-1 in chronically active brain lesions (Cannella and improve vascular function and prevent subsequent neurodegeneration. Raine, 1995; Kuenz et al., 2005). The role of ICAM-1 and VCAM-1 In MS and stroke, where the role of the vasculature in the early stages upregulation has been investigated in the commonly used experi- of disease is clearer, there have also been some direct clinical and pre- mental autoimmune encephalomyelitis (EAE) in vivo model of MS, clinical trials of drugs aimed at reducing endothelial inflammation and confirming that these molecules assist in the penetration of leukocytes thereby limiting neurodegeneration. Major targets of these approaches through the BBB and exacerbate neuroinflammation ( Doerck et al., are the CAMs and this has already been shown to be therapeutically 2010). Moreover, a meta-analysis of MS genome-wide association effective in MS, where Natalizumab, a monoclonal antibody which studies identified key CAM biological pathways to be highly enriched blocks interaction of VCAM-1 with its ligand very-late antigen-4 (VLA- and linked to MS susceptibility (Damotte et al., 2014). In contrast, work 4), is one of the main therapeutic agents used (Brandstadter and Katz, in this area in PD patients is limited to one recent small, and therefore 2017). This therapy reduces disease progression, as well as the number underpowered, study (Yu et al., 2020). The study found abnormally high of relapses and development of brain lesions in relapsing remitting MS expression of vascular inflammatory markers, including VCAM-1, in the (Polman et al., 2006; Rudick et al., 2006; Nicholas et al., 2022). How- peripheral blood. This correlated with disease severity and with specific ever, it is not authorised for use against secondary-progressive MS due to regional brain atrophy (Yu et al., 2020). In AD, there has been sub- lack of efficacy (Kapoor et al., 2018), implying a primary function in stantial assessment of CAMs (ICAM-1 and VCAM-1) in the plasma and preventing neurological damage following initial neuroinflammatory CSF (reviewed by Custodia et al., 2023), that appear to correlate with events. rapid progression of cognitive impairment (Drake et al., 2021). Post-mortem tissue from ischemic stroke patients (collected between 5 M. Ritson et al. Journal of Neuroimmunology 391 (2024) 578363 15 h and 18 days post-stroke), exhibits a substantial increase in cerebral risk factor for NDDs (Li et al., 2015; Verdile et al., 2015). Insulin sig- endothelial ICAM-1 expression (Lindsberg et al., 1996). The role of nalling is imperative for optimal cerebral EC and neuronal function ICAM-1 in neurodegeneration following stroke is supported by a rodent (Rhea and Banks, 2019). Decreased expression of insulin receptors in the study using a middle cerebral artery occlusion (MCAO) model of stroke, brain microvasculature of mice in vivo alters insulin signalling within the where treatment with an anti-ICAM-1 antibody significantly reduced brain (Konishi et al., 2017). Disruption to insulin signalling is common brain damage and the presence of leukocytes within lesions (Zhang to both diabetes and AD pathology (Arnold et al., 2018). In addition, et al., 1994). However, it should be noted that ICAM-1 is also expressed hyperglycaemia-induced production of compounds such as methyl- by some immune cells (macrophages and lymphocytes) so ICAM-1 in- glyoxal, a harmful oxoaldehyde, exacerbate endothelial dysfunction due hibition, unless targeted to ECs alone, will also affect these cell types. to increased cellular apoptosis and oxidative stress, therefore increasing Elevated ICAM-1 concentrations have also been reported in the sera of the risk of PD (Sabari et al., 2023). A murine model of type 2 diabetes acute ischemic stroke patients and associate with poor prognosis (Wang has shown extensive damage to BBB structure, occurring due to the et al., 2021). Despite these data, reducing CAM activation is not uni- increased presence of pro-inflammatory mediators and an altered im - versally protective. A clinical trial evaluating the treatment of ischemic mune response (Sheikh et al., 2022). The in vitro and in vivo models of stroke patients with Enimomab, an anti-ICAM-1 therapy, showed that type-2 diabetes studies in the work of Sheikh et al. (2022) both show a treatment led to more adverse events and a higher chance of death loss of tight junction protein expression and an increased influx of (Enlimomab Acute Stroke Trial, 2001). This variance is likely due, at neutrophils into the brain parenchyma (Li et al., 2022). These effects least in part, to the limitations of the real-world clinical environment, were reversed by either pharmacological intervention with recombinant where treatment is not given immediately after stroke (delayed until as ANXA1 (a mediator of glucocorticoid anti-inflammatory mechanisms, late as 6 h post stroke onset in this example); earlier initiation of known to reduce BBB leakage) or dietary reversion of the diabetes treatment may have led to a different outcome. Delayed treatment of phenotype (Sheikh et al., 2022). If early stages of metabolic disease, mice with anti-VCAM-1 in a model of ischemia-induced vascular de- such as diabetes, can cause systemic inflammation and BBB damage, mentia found significant reductions in neuroinflammation and cognitive then it is possible that undiagnosed or poorly controlled diabetes may decline, although early intervention with anti-VCAM-1 did not produce results in prolonged injury to the brain. This chronic systemic challenge the same effects (Zera et al., 2021). Together, these data indicate a time- to the cerebrovasculature may also have other actions to increase risk to dependence in the use of CAMs as a therapeutic target. Furthermore, no cerebral disease (see below) and warrant further investigation. protection against ischemic stroke, nor a difference in accumulation of Studies utilising animal models of chronic systemic inflammation inflammatory cells was found when the MCAO model was applied to have reported increased cognitive impairment and enhanced expression null transgenic ICAM-1 deficient mice (Enzmann et al., 2018), suggesting of dementia-associated risk factors (Sy et al., 2011; Marottoli et al., the existence of a more complex relationship between adhesion mole- 2017). The effect of systemic inflammation on the BBB has been cules, leukocyte infiltration and injury severity than is currently modelled in mice using peripheral injections of LPS (Nonaka et al., 2005; recognised. Qin et al., 2007; Franciosi et al., 2012; Banks et al., 2015; Zhao et al., 2019). There is evidence that neuroinflammation can significantly alter multiple BBB transport systems, such as those for insulin, TNF and 7. Can systemic disease push endothelial cells to dysfunction and affect the incidence, severity or onset of neurodegenerative amyloid beta peptide, and that these changes are further exaggerated with repeated exposure to LPS in vivo as opposed to a single high-dose disorders? LPS exposure (Xaio et al., 2001; Pan et al., 2008; Jaeger et al., 2009). In a transgenic animal model of AD, repeated low-medium dose LPS The association between chronic systemic inflammation and vascular disease is one that has been well documented (Petek et al., administration (0.5 mg/kg) over a 2-month period produced significant cerebrovascular injury, including increased vessel leakage and protein 2022). Findings from studies using models of NDDs alongside clinical data suggest that ongoing systemic inflammation may also exacerbate deposition in the parenchyma, alongside cognitive deficits (Marottoli et al., 2017). More work is required to understand the links between the occurrence and progression of neurological disorders via actions on the cerebrovasculature. This may occur via a number of mechanisms systemic inflammation and subsequent neurodegeneration, including the level of plasticity and repair possible within the cerebrovasculature, (some of which are discussed below), but more epidemiological studies how early irreparable vascular damage occurs, and the role of molecular are required to understand how systemic disease affects an individuals’ priming of endothelial inflammatory response as a contributor to the risk burden for neurological disease. Specifically, it is not yet clear severity of later injury. Processes of tolerance and sensitisation are whether systemic disease has a contribution of sufficient magnitude to increase the number of people who may later develop a neurodegener- known to affect inflammatory signalling following repetitive exposure (Gillen et al., 2021; Nürnberger et al., 2021; De Zuani et al., 2022; Li ative condition, or whether it interacts with other risk factors to affect the severity and/or timing of disease onset. et al., 2023). Which of these, if any, occur in cerebral ECs following repetitive or chronic (peripheral or central) inflammation has not yet One mechanism by which inflammation may lead to cerebrovascular dysfunction and NDDs is through the production of ROS, leading to a been established, but the outcomes of such studies will be critical for understanding mechanisms of endothelial dysfunction and whether el- state of oxidative stress (Song et al., 2020). Systemic oxidative stress has been associated with reduced ocular hemodynamic flow, linked to ements of the endothelial signalling pathways referenced above are potential candidates for effective therapeutic targeting. increased vascular permeability in patients with glaucoma (Himori et al., 2015). Neurodegeneration in NDD mouse models and patients, is As an additional factor, aging also affects the immune response and the cerebral vasculature (Malaguarnera et al., 2001). Aging is accom- associated with changes in oxidative stress and mitochondrial dysfunc- panied by an increase in cellular senescence, where cells undergoing tion (Henchcliffe and Beal, 2008; Elstner et al., 2011; Grammas et al., senescence release pro-inflammatory cytokines, promoting a chronic 2011; Reeve et al., 2013; Chang and Chen, 2020; Ahn et al., 2023). inflammatory state (Childs et al., 2015). Increasing proportions of se- Similarly, oxidative stress in ischemic stroke it has been proposed to heighten neuroinflammation through release of ROS, increasing pro - nescent cells appears to be a driving force in the progression of age- associated disorders which include atherosclerosis and NDDs (Saez- grammed cell death following ischemic injury. Although the molecular mechanisms behind this interplay are not known (reviewed by Wu et al., Atienzar and Masliah, 2020; Wissler Gerdes et al., 2020). Yamazaki et al. (2016) using an in vitro BBB model comprised of senescent primary cells, 2020). There is an accumulation of evidence linking diabetes, a primary highlighted an exacerbation of senescence in ECs, leading to decreased tight junction coverage and increased BBB disruption (Yamazaki et al., metabolic disorder, to cerebrovascular and cognitive disorders. Diabetes is characterised by dysregulated insulin signalling and is a recognised 2016). Additionally, in a senescence prone mouse model, it was found 6 M. Ritson et al. Journal of Neuroimmunology 391 (2024) 578363 that altered CBF arising from aging and vascular insult, correlated with a Acknowledgements decline in cognitive dysfunction (Zhang et al., 2013).Therefore the as- sociation between EC senescence, cerebrovascular inflammation, and None. increased BBB permeability is one that is well-established and requires further exploration in the context of early-life systemic disease and the References subsequent risk burden for NDDs (Graves and Baker, 2020; Han and Ahmad, A., Patel, V., Xiao, J., Khan, M.M., 2020. The role of neurovascular system in Kim, 2023). neurodegenerative diseases. Mol. Neurobiol. 57 (11), 4373–4393. Given the interplay between systemic inflammatory disease, acute Ahn, J.H., Kang, M.C., Lee, D., Cho, J.W., Park, K.A., Youn, J., 2023. 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Journal of Neuroimmunology 391 (2024) 578363 Contents lists available at ScienceDirect Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim Endothelial dysfunction in neurodegenerative disease: Is endothelial inflammation an overlooked druggable target? Megan Ritson , Caroline P.D. Wheeler-Jones , Helen B. Stolp Department of Comparative Biomedical Sciences, Royal Veterinary College, London NW1 0TU, UK ARTICLE INFO ABSTRACT Keywords: Neurological diseases with a neurodegenerative component have been associated with alterations in the cere- Neurodegeneration brovasculature. At the anatomical level, these are centred around changes in cerebral blood flow and vessel Endothelium organisation. At the molecular level, there is extensive expression of cellular adhesion molecules and increased Blood-brain barrier release of pro-inflammatory mediators. Together, these has been found to negatively impact blood-brain barrier Inflammation integrity. Systemic inflammation has been found to accelerate and exacerbate endothelial dysfunction, neuro - Cerebrovascular inflammation and degeneration. Here, we review the role of cerebrovasculature dysfunction in neurodegener - ative disease and discuss the potential contribution of intermittent pro-inflammatory systemic disease in causing endothelial pathology, highlighting a possible mechanism that may allow broad-spectrum therapeutic targeting in the future. 1. Neurodegeneration and the cerebrovasculature neurodegenerative disorders via several processes (reviewed by Ware- ham et al., 2022), and have been suggested to play a critical role in the The prevalence of neurological disease with a neurodegenerative aetiology of these conditions (Drouin-Ouellet et al., 2015; Hatate et al., component is rapidly increasing due to the aging global population 2016). More work is required to definitively support this link, which is (Wyss-Coray, 2016). This collection of primarily sporadic diseases partly strengthened by the increasing evidence that vascular dysfunction affecting the central nervous system (CNS) are often characterised by is an early part of disease pathophysiology (Kelleher and Soiza, 2013; ´ ´ neurodegeneration of neuronal populations or axonal processes, across a Apatiga-Perez et al., 2022; Yuan et al., 2023). If true, a renewed focus on lifespan (Heemels, 2016). The most common examples include Alz- the cerebrovascular contribution to NDDs may add to our understanding heimer’s disease (AD), Parkinson’s disease (PD) and Multiple Sclerosis of disease aetiology and treatment options. As the interface between the (MS) (DeTure and Dickson, 2019; Simon et al., 2020; Mey et al., 2023). brain and the rest of the body, the endothelial cells (ECs) that make up In addition, secondary neurodegeneration can arise following a large the cerebrovasculature are exposed to a plethora of minor (and major) vascular injury such stroke (Ong, 2022). Neurological diseases with a insults across a lifetime that may alter their function and disrupt the substantial degenerative component (from here on termed neurode- neuronal cells they protect. Equally, the ECs of the blood-brain barrier generative diseases, NDDs), are diverse in presentation and pathology, (BBB), unlike the neuronal cells beyond this barrier, are a highly drug- causing an array of life altering symptoms including memory impair- gable target and therefore may represent a future theragnostic target, ment, cognitive deficits, loss of motor function and respiratory compli - exploitable both as a diagnostic biomarker and for a disease modifying cations (Erkkinen et al., 2018). Treatment options for these conditions treatment. are primarily limited to symptom management (Wareham et al., 2022). In this broad review, we discuss the role of ECs in regulating cere- New therapies directly targeting disease processes have recently been brovascular function, summarise the evidence for cerebrovascular identified for AD, though it remains unclear how efficacious these will dysfunction in NDDs and suggest mechanisms by which ECs may be in clinical practice given limitations of diagnostic capacity (Larkin, contribute to this. We also make a link between systemic disease and 2023; van Dyck et al., 2023). There is, therefore, a pressing need for endothelial injury, a mechanism through which repeated peripheral novel therapeutic approaches. inflammation may contribute to NDD severity and progression that Alterations within the cerebral microvasculature may contribute to could be exploited in the future to diagnose and treat patients. * Corresponding author at: Department of Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London NW1 0TU, UK. E-mail address: [email protected] (H.B. Stolp). https://doi.org/10.1016/j.jneuroim.2024.578363 Received 21 December 2023; Received in revised form 29 March 2024; Accepted 2 May 2024 Available online 3 May 2024 0165-5728/© 2024 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). M. Ritson et al. Journal of Neuroimmunology 391 (2024) 578363 2. The endothelium, blood-brain barrier, and neurovascular periphery (Andreone et al., 2017) and have a high presence of efflux unit transporters which restrict access of specific lipophilic molecules to the brain (Qosa et al., 2015). As a counter to this restrictive barrier, brain The endothelium, a monolayer of ECs, lines the luminal surface of all ECs express multiple transporters to support the active movement of blood vessels within the body, forming the critical interface between the specific solutes in and out of the brain and consequently have a high blood and the tissue, and orchestrating vascular function. ECs have a mitochondrial density (Kadry et al., 2020). Together, these specialisa- heterogeneity of structure and function which has been described at the tions allow the ECs of the BBB to protect the CNS from fluctuations in the morphological, functional, and genomic levels (Aird, 2012; Jambusaria systemic environment (Lansdell et al., 2022), and disruption in these et al., 2020). Signals from within the tissue microenvironment, such as mechanisms are hallmarks of neurodegenerative conditions. those generated through cell-cell interactions, together with release of While there are many factors that may lead, at a cellular level, to growth factors, can influence tissue-specific adaptations of ECs (Potente altered vascular function or disruption of the BBB, this review focuses on and Makinen, 2017), enabling them to perform various physiological inflammation as a process with important commonality to systemic roles in tissues including the modulation of vascular tone, platelet ag- disease and NDDs. Many systemic conditions that are associated with gregation, angiogenesis, leukocyte trafficking and other responses to vascular injury in the periphery, such as diabetes and high serum inflammation (Ait-Oufella et al., 2010; Sturtzel, 2017). cholesterol, result in increased circulating inflammatory mediators that In terms of their contribution to vascular tone, and therefore regional will inevitably interact with the cerebral ECs (Que et al., 2018; Sheikh blood flow, healthy ECs produce multiple vasoactive mediators that act et al., 2022). When sufficiently severe, systemic inflammation results in on surrounding contractile cells to either constrict or dilate the blood acute, transient inflammation of the cerebral endothelium (Verma et al., vessels (see Sandoo et al., 2010 for a review on the molecular regulation 2006) and altered function of the cerebrovasculature and the BBB of these processes). Many of these actions typically occur in arterioles (Sheikh et al., 2022; Banks et al., 2015). Normal aging and neuro- and post-capillary venules through modulation of smooth muscle cell degeneration also cause inflammation of systemic and cerebrovascular function, regulating blood flow at a mesoscale, and are common across ECs (see Finger et al., 2022), and acute systemic inflammation can vascular beds. In the cerebrovasculature, there is additional regulation reactivate dormant neuroinflammatory lesions (Serres et al., 2009) and of blood flow via neurovascular coupling at the level of the capillary affect amyloid clearance from the brain (Erickson et al., 2012), sug- which is utilised to regulate and maintain regional cerebral blood flow gesting a complex interplay between (systemic) inflammation and (CBF) in response to local activity (Otsu et al., 2015; Iadecola, 2017; neurological injury. Ahmad et al., 2020; Stackhouse and Mishra, 2021). The vascular endothelium is a key modulator of the acute inflam - Within the neurovascular unit (NVU; Fig. 1), the ECs are specialised matory response, promoted by abnormal physiological stimuli, damage, compared to those in most peripheral vascular beds and form the BBB, or infection (Leick et al., 2014). A recent analysis of peripheral and the regulated interface between the peripheral circulation and the CNS cerebral endothelial inflammatory responses suggests that a subset of (Macdonald et al., 2010; Koizumi et al., 2016). ECs exhibit continuous ECs may even have a specific immunomodulatory role (Amersfoort junctions between adjacent cells, sealed by tight junction complexes, et al., 2022), possibly contributing to immune surveillance as well as which are important for creating a functional anatomical barrier into the tissue pathology. During acute inflammation, there is increased release brain (Liu et al., 2012). There is a substantial body of work on the nature of pro-inflammatory cytokines and upregulation of cellular adhesion of these junctions (for a recent review see Lochhead et al., 2020), with molecule (CAM) expression. These processes occur in all vascular beds, the presence and structural organisation of claudin and occludin pro- the underlying molecular mechanisms at the BBB have been well teins considered particularly essential for junctional integrity. ECs described (Dietrich, 2002; Müller, 2019; Wimmer et al., 2019). within the CNS also demonstrate low rates of vesicle transport, due to Numerous transcriptomics studies in rodent models of acute systemic the inhibition of caveolae-mediated transcytosis regularly utilised in the inflammation have added to our understanding of the early (Kodali et al., 2020; Struck et al., 2024) and later stages (Munji et al., 2019) of endothelial inflammatory signalling. These studies show that at base - line, genes associated with chemokine signalling, antigen presentation and leukocyte diapedesis (e.g. ICAM-1, VCAM-1, CCL2) are more highly expressed in peripheral vessels compared to cerebral ECs (Munji et al., 2019). Cerebral ECs up-regulate pathways associated with nuclear fac- tor- kappa B (NF-κB) signalling within 15 min of a peripheral inflam - matory stimulus followed, at later time points, by genes governing cytokine and chemokine production and leukocyte migration (Kodali et al., 2020), similar to changes observed in peripherally derived ECs (Struck et al., 2024). Overall, current evidence implied that cerebral ECs appear adopt a phenotype comparable to that of peripheral ECs following systemic challenge, with down regulation of BBB-enriched genes and increases in inflammatory genes (Munji et al., 2019). It should be noted that the majority of studies in models of vascular inflammation utilise high concentrations of lipopolysaccharide (LPS) or TNF. As a result, the timing, magnitude and composition of the endo- thelial inflammatory response would likely vary in more disease specific injury models or in patient responses. Generally, the acute inflammatory response is confined and benefi - cial, providing protection from pathogenic stimuli, particularly in the periphery. However, if inefficient resolution occurs, detrimental chronic Fig. 1. The Neurovascular Unit. inflammation can develop. At the microvascular level, endothelial Schematic illustration of the neurovascular unit (NVU) at the microvascular dysfunction is evident, characterised by a prolonged increased in the level. The NVU is comprised of endothelial cells, the basal lamina, pericytes, release of pro-inflammatory cytokines, impaired production of vasodi - astrocyte endfeet, neurones and microglia. These different components work lators, increased generation of vasoconstrictor molecules as well as together to maintain homeostasis of the brain microenvironment (Adapted from Dubois et al., 2014). upregulated expression of CAMs (Steyers and Miller Jr, 2014; Bennett 2 M. Ritson et al. Journal of Neuroimmunology 391 (2024) 578363 et al., 2018). In the periphery these changes have been well-described as The data from patients with neurodegenerative disease, as well as contributing to increased vasoconstriction and to enhanced leukocyte animal and cell models of these diseases is currently fragmentary (dis- migration, capillary permeability, and platelet aggregation (Pober and cussed in detail below). In order to reduce endothelial dysfunction in Sessa, 2007). Combined, these altered functions are responsible for the neurodegenerative diseases, it is important to understand and determine extensive damage exhibited in chronic inflammatory diseases in the how and when processes of endothelial dysfunction occur, whether the periphery such as atherosclerosis and rheumatoid arthritis (Murdaca common inflammatory pathways are activated equally in each condi - et al., 2012; Nikpour et al., 2013; Steyers and Miller Jr, 2014). tion, and if early-life injuries or systemic disease may alter the timing or Leukocyte transmigration, following increases in cytokine signalling magnitude of the cerebral endothelial response. This knowledge can be and upregulation of CAMs, is recognised to occur in the brain and used to identify early markers of the disease process and to investigate contributes to neurological disease, particularly in MS and stroke vascular targeted therapies as disease modifying agents. Therapeutic (Juurlink, 1998; Schmitt et al., 2012; Sienel et al., 2022; Fig. 2). While agents are already available that could be used to counter the detri- these pathways are not as active in physiological or low-inflammatory mental effects of a range of inflammatory mediators e.g. TNF (Chou states as in the periphery, leading to the original hypothesis of et al., 2016) and IFNGR1 (YetkIn and Gültekin, 2020), if stronger evi- immune-privilege in the brain, they can be substantially upregulated in dence for their involvement in the disease process merges. the brain under pathological conditions (recently reviewed in detail in Ludewig et al., 2019). The signalling pathways regulating trans- 3. Evidence for and against altered cerebral blood flow in migration, and the downstream consequences of this for cerebrovascular cerebrovascular and neurodegenerative diseases and parenchymal damage have been extensively reviewed elsewhere (Man et al., 2007; Larochelle et al., 2011; Takeshita and Ransohoff, In the absence of accessible and effective methods for measuring 2012). CBF, many studies investigating vascular dysfunction in neurodegener- The structural and functional alterations in the cerebral endothelium ative disease have focused on measuring peripheral endothelial function have been shown to lead to increased inflammation and oxidative stress, using flow-mediated dilation (FMD), a non-invasive ultrasonography which together severely impair neurovascular function (Lehner et al., technique that measures endothelium-dependent relaxation of the 2011; Liu et al., 2012). Dysfunction of the BBB is characterised by the brachial artery following reactive hyperemia. The difference in diameter loss of tight junction integrity, increased permeability, upregulated in the brachial artery compared to the basal diameter is considered to be transcytosis and increased CAM expression leading to an influx of in - the FMD, with an FMD value <7.8% being the cut-off for the diagnosis of flammatory mediators into the brain (Daneman, 2012; Koizumi et al., endothelial dysfunction (Korkmaz and Onalan, 2008; Mucka et al., 2016). 2022). In PD, FMD has been found to be significantly lower in patients Fig. 2. Mechanisms of endothelial inflammation in NDDs. Multiple mechanisms of endothelial inflammation have been confirmed to be present in different NDDs. Pro-inflammatory cytokines (e.g. TNF, IL-6) bind to their corresponding receptors on the endothelial cell surface (Aref et al., 2020; Magliozzi et al., 2021), shown to lead to the activation and translocation of NF-κB to the nucleus. As a consequence, this initiates transcription of genes hypothesised to be involved in the downstream functional changes arising from endothelial cell inflammation (Srinivasan et al., 2017; Zhou et al., 2023). The activation of the NF-κB pathway can also lead to the upregulation in the expression of cellular adhesion molecules (CAMs) such as ICAM-1 (Frohman et al., 1991; Lindsberg et al., 1996). Upregulation of CAMs facilitates the transmigration of leukocytes into the tissues (Brock et al., 2015; Quan et al., 2019), alongside the release of pro-inflammatory mediators (Grammas and Ovase, 2001). Additionally, inflammatory expression of von-Willibrand factor (vWF) mediates platelet activation and aggregation within the vessel (Mari et al., 1996; Sevush et al., 1998; Morel et al., 2015). The release of reactive oxygen species (ROS) occurs due to the uncoupling of endothelial nitric oxide synthase (eNOS), consequently leading to a decrease in nitric oxide (NO) and a state of oxidative stress (Szolnoki et al., 2005; Tan et al., 2015). 3 M. Ritson et al. Journal of Neuroimmunology 391 (2024) 578363 compared to age matched control subjects (7.1% compared to 8.1% in the brain after stroke, there is substantial evidence of systemic respectively) (Yoon et al., 2015). A small case-control study found AD vascular dysfunction contributing to the risk of stroke. Specifically, patients free of vascular risk factors to have lower FMD values than those atherosclerotic vascular changes (Libby et al., 2019), are a well- of control patients (3.45% compared to 8.41%, respectively) (Dede established risk factor for (non-cardioembolic) ischemic stroke, with et al., 2007). Disease severity, in particular lower scoring on cognitive ~70% of patients showing a substantial aortic plaque burden, and ~ tests, has also been reported to correlate with the decreased FMD values 20% having severe internal carotid artery stenosis (Serena et al., 2015). found in AD patients (Dede et al., 2007; Tachibana et al., 2016). Overall, The combination of high body mass and diabetes (both risk factors for these findings suggest that peripheral endothelial dysfunction, assessed atherosclerosis), as well as the presence of symptomatic peripheral ar- by FMD, is associated with multiple risk factors of AD. tery disease and intracranial artery stenosis, have all been identified as With respect to the brain, the obvious limitation of FMD is that it is a common risk factors for further stroke events occurring within a 12- measurement of peripheral endothelial dysfunction, and does not month period (Serena et al., 2015). directly indicate CBF or indeed other regional changes in brain blood While atherosclerosis is a systemic condition, and in part contributes flow associated with disease states. Technological advances in arterial to stroke risk by increasing the chance of a thrombotic event, the data spin labelling magnetic resonance imaging (ASL-MRI) have allowed the overall suggest that there may also be early changes occurring within the detection of a posterior hypoperfusion condition in PD patients within cerebral vascular beds that increase the risk of an ischemic occlusion. the parietooccipital cortex and posterior cingulate cortex (Kamagata This idea is supported by data from a meta-analysis that followed stroke et al., 2011; Arslan et al., 2020). A broader pattern of altered blood flow free individuals over a 5–12 year period, assessing the retinal vessels as has been reported by others (Wei et al., 2016), although not specifically biomarkers for stroke risk. Altered vessel calibre, specifically increased within the substantia nigra. These studies have shown that regional venular calibre was shown to be an independent risk factor for stroke hypoperfusion occurs in cognitively normal PD patients, and the degree (McGeechan et al., 2009). As many of the factors that contribute to of hypoperfusion is strongly correlated with mild cognitive impairment atherosclerosis also affect local vessel function (e.g., inflammatory cy - or dementia in addition to the PD diagnosis (Kamagata et al., 2011; tokines, increased ROS, enhanced leukocyte and platelet adhesion, Arslan et al., 2020). reduced nitric oxide production; Roquer et al., 2009), it is possible that Regional changes in CBF have also been measured using ASL-MRI in while atherosclerotic burden can increase the risk of stroke, much of this AD patients, with a recent meta-analysis indicating that reductions in risk arises directly from altered reactivity within the cerebrovascular blood-flow occur with normal aging and are exacerbated in AD, though beds. Current preventative treatments for cerebral small vessel disease with high variability in the affected brain regions reported between and their sequalae are largely focused on reducing risk factors, such as studies (Graff et al., 2023; Swinford et al., 2023). Altered regional CBF clot formation and reducing cholesterol (Smith and Markus, 2020). The has also been demonstrated using neuroimaging in patients following assessment of retinal vessel calibre provides proof-of-principle that stroke (Nakaoku et al., 2018), or who have been diagnosed with MS assessing vascular structure can provide insights into disease risk and - could lead to identification of more focused biomarkers related to (Zhang et al., 2018). However, it is difficult to make definitive state ments as to the location and magnitude of these changes given the vascular function, probably as part of a multi-tiered screening for early variation in presentation and evolution of these conditions compared to diagnosis and preventative therapy. In line with this aim, trials of allo- those studies conducted in PD and AD patients. purinol and cilostazol are currently being performed in patients with In AD, there has been a greater depth of research into the nature of cerebral small vessel disease to reduce endothelial inflammation and vascular disruption leading to altered regional CBF (reviewed by Korte increase the capacity to regulate vascular tone (reviewed in Smith and et al., 2020). There is clear evidence that damage to the capillaries can Markus, 2020). A similar change in therapeutic approach may be useful occur as a secondary response to amyloid deposition in AD patients in AD, where research utilising vessel size imaging to quantify vessel (Kimura et al., 1991), and cerebral amyloid angiopathy (CAA), the structure in an AD mouse model found decreased density and abnormal deposition of amyloid beta (Aβ) plaques on the walls of both brain ar- morphological changes in the microvessels at both early and late stages terioles and capillaries, is present in 90% of AD cases (Grinberg and of disease (Xu et al., 2020). Thal, 2010). This Aβ deposition can directly reduce CBF in both ex vivo Substantial disruption of BBB integrity is evident in most neurode- and in vivo AD models (Suo et al., 1998; Dietrich et al., 2010) by evoking generative disorders and commonly results in increased leakage of vasoconstriction through increased reactive oxygen species (ROS) pro- serum proteins into the brain. In PD patients, post-mortem analysis or in duction by the cerebral arteries (Niwa et al., 2001). In turn, this vivo MRI have specifically shown altered BBB permeability in the reduction in CBF increases the production of Aβ in vivo, forming a striatum and substantial nigra (Gray and Woulfe, 2015; Al-Bachari et al., damaging feedback loop (Sun et al., 2006; Zhang et al., 2007). At the 2020). A recent study has reported increased BBB leakage in a PD mouse capillary level, Aβ acts at pericyte-dense locations to cause constriction model with global overexpression of human alpha-synuclein (α-syn), a (in both human AD and mouse models) via a mechanism involving NOX- key protein involved in PD pathology (Gomez-Benito et al., 2020; Elabi 4-dependent reactive oxygen species (ROS) production and downstream et al., 2021). This was accompanied by localisation of α-syn within ECs, release of endothelin-1 (Nortley et al., 2019). The molecular and cellular inappropriate pericyte activation, and dynamic alterations in vessel mechanisms responsible for the reduced CBF in other NDDs remain to be density starting relatively early in the aging process (Elabi et al., 2021). determined. Interestingly, the authors showed increased vessel density at 8-months and decreased density at 13-months, potentially explained by an 4. Evidence for structural reorganisation of the initial increase in compensatory angiogenesis in the early stages of disease followed by vascular regression in the later stages (Elabi et al., cerebrovasculature and blood-brain barrier in 2021). These observations clearly place alterations in the cere- neurodegenerative disorders brovasculature as an early part of PD disease pathophysiology. The use of advanced neuroimaging in both human AD patients and Altered CBF in a pathological scenario may result from changes in vascular wall structure, affecting the compliance to modulatory signals AD animal models has identified breakdown of the BBB in early disease states (van de Haar et al., 2016; Alkhalifa et al., 2023). Deposition of Aβ from the endothelium. It is likely that these pathological alterations in tissue structure, along with associated modifications in local endothelial plaques has been directly associated with an increase in BBB perme- ability (Roher et al., 2003; Carrano et al., 2011; Zenaro et al., 2017). signalling, contribute to the measured changes in regional CBF discussed above. Similarly, in a rat BBB in vitro model, treatment with human tau increased endothelial permeability (Kovac et al., 2009). Decreases in The clearest data in this area come from investigations into the initiating factors of stroke. In addition to vascular disruption occurring both claudin-5 and occludin expression have been found in post-mortem 4 M. Ritson et al. Journal of Neuroimmunology 391 (2024) 578363 analyses of AD patient brains and are associated with increased Microvessels isolated from the brains of AD patients also show high permeability of the BBB (Yamazaki et al., 2019). In addition, a single levels of pro-inflammatory cytokines (Grammas & Ovase), and histo- intravenous injection of claudin-5 produced acute improvements in both logical studies in tissue from AD patients have reported elevated ICAM-1 learning and memory in the APP/PS1 mouse when assessed 1–4 days (reviewed in Grammas, 2011). post treatment (Zhu et al., 2022). While vascular inflammation is evident in these conditions, the onset BBB disruption has been recognised as a key component of MS and extent of inflammation in the aetiology of neurodegeneration re - pathophysiology (Claudio et al., 1995; Werring et al., 2000; Vos et al., mains a point of discussion. While many of the findings described above 2005a, 2005b; Cramer et al., 2015), typically considered a consequence reflect the response to cerebral injury and degeneration, there is also of the high level of leukocyte diapedeses. Investigations using gadolin- evidence of vascular inflammation indirectly contributing to the disease ium (Gd)-MRI to assess MS lesions recognised intense focal disruptions process and driving neuronal damage. Data in support of this are within the BBB, primarily centred around sites of extensive neuro- accumulating from studies on AD and stroke. In particular, cerebral ECs inflammation (Grossman et al., 1986; Miller et al., 1998). A study using isolated from AD patients have been reported to release toxic factors, dynamic-contrast MRI revealed a correlation between BBB disruption causing neuronal injury (Kelleher and Soiza, 2013), although the iden- and the appearance of MS lesions with disease relapse (Cramer et al., tity of these factors is yet to be confirmed. In vitro studies using micro- 2013). Gd-enhancing MRI techniques have also documented BBB vessels from AD patients showed that vascular-mediated neuronal death breakdown in the normal white matter as well as white matter lesions in occurred when naïve neurons were cultured directly with AD micro- MS patients (Lund et al., 2013; Choi et al., 2021), indicating a broader vessels, or with their conditioned media (Grammas, 2000). Additional in cerebrovascular dysfunction in this condition than the acute inflam - vitro work investigating pro-inflammatory cytokine-mediated activation matory lesions might suggest. Consistent with these MRI studies, post- of cerebral ECs has also demonstrated the release of neuron-toxic factors mortem histology has shown a decrease in the expression of the tight from ECs, leading to death of cholinergic neurons. These studies indicate junction proteins occludin and ZO-1 in the microvessels within active a role for the cerebral vasculature in contributing to the degeneration of MS lesions. Abnormalities in the structure of these tight junctions were cholinergic neurons observed in AD (Moser et al., 2006). These in vitro identified in ~40% of the vessels, including in white matter with a approaches suggest a direct role for the endothelium in the neuronal normal appearance (Plumb et al., 2002; Kirk et al., 2003). Tight junction death that underpins NDD aetiology. There is research in animal models abnormalities are associated with an increased leak of serum fibrinogen that have investigated the effects of systemic inflammation on the ce - within MS lesions (Vos et al., 2005a, 2005b; McQuaid et al., 2009). It has rebral vasculature, as discussed below (Marottoli et al., 2017), or the been suggested that increased entry of mediators such as fibrinogen into contribution of inflammation to neurodegeneration (Kitazawa et al., the CNS, resulting from continuously increased BBB permeability, can 2005; Catorce and Gevorkian, 2016; Huang et al., 2024). However, lead to the progressive demyelination characterising MS pathology, and further research into the involvement of early life vascular inflammation exacerbates neuroinflammation (Kirk et al., 2003). While there is clear and its link to neurodegenerative disease in later life is now warranted. evidence of loss of tight junction proteins in MS, a longitudinal case- control study of tight junction proteins in the blood of MS patients 6. Does altering endothelial cell or vascular function affect showed increased circulating levels of these proteins, but there was no neurodegenerative disease outcomes? clear correlation with MS disease severity (Olsson et al., 2021), limiting their potential use as diagnostic biomarkers in this condition. There is, To date, improvements in vascular function in NDDs have been therefore, need of further work in this, as in other neurodegenerative assessed following treatment of the non-vascular related elements of the conditions, to identify biomarkers of disease that can facilitate diagnosis disease process, thereby reducing the secondary vascular injury that and monitoring of disease progression and treatment. A more detailed occurs following neurodegeneration. For instance, a study using a mouse understanding of vascular injury may provide candidates for these new model of AD showed preservation of BBB integrity when tau is sup- biomarkers. pressed (Blair et al., 2015). Similarly, in an in vitro study using human brain ECs Aβ was shown to influence the integrity of the BBB primarily 5. Evidence for inflammatory injury as a driver of endothelial through the disruption of tight junction proteins such as claudin-5 cell dysfunction in neurodegenerative disorders (Griffin et al., 2016). Current therapies targeting the Aβ-induced neuropathology such as Lecanemab (an immunotherapy, targeting Aβ to In common with BBB breakdown, neuroinflammation has been slow AD progression; van Dyck et al., 2023) may therefore be effective identified in the cerebrovasculature in all the NDD conditions discussed, both through reducing primary disease and limiting exacerbation that though the body of evidence is greater in some than others. In MS, would otherwise follow amyloid-induced alterations in BBB integrity. A increased expression of CAMs and the associated leukocyte diapedesis question remaining, is whether therapies aimed at directly reducing BBB are well recognised. This is due in part to the presence of high levels of breakdown or other early stages of endothelial dysfunction, could ICAM-1 and VCAM-1 in chronically active brain lesions (Cannella and improve vascular function and prevent subsequent neurodegeneration. Raine, 1995; Kuenz et al., 2005). The role of ICAM-1 and VCAM-1 In MS and stroke, where the role of the vasculature in the early stages upregulation has been investigated in the commonly used experi- of disease is clearer, there have also been some direct clinical and pre- mental autoimmune encephalomyelitis (EAE) in vivo model of MS, clinical trials of drugs aimed at reducing endothelial inflammation and confirming that these molecules assist in the penetration of leukocytes thereby limiting neurodegeneration. Major targets of these approaches through the BBB and exacerbate neuroinflammation ( Doerck et al., are the CAMs and this has already been shown to be therapeutically 2010). Moreover, a meta-analysis of MS genome-wide association effective in MS, where Natalizumab, a monoclonal antibody which studies identified key CAM biological pathways to be highly enriched blocks interaction of VCAM-1 with its ligand very-late antigen-4 (VLA- and linked to MS susceptibility (Damotte et al., 2014). In contrast, work 4), is one of the main therapeutic agents used (Brandstadter and Katz, in this area in PD patients is limited to one recent small, and therefore 2017). This therapy reduces disease progression, as well as the number underpowered, study (Yu et al., 2020). The study found abnormally high of relapses and development of brain lesions in relapsing remitting MS expression of vascular inflammatory markers, including VCAM-1, in the (Polman et al., 2006; Rudick et al., 2006; Nicholas et al., 2022). How- peripheral blood. This correlated with disease severity and with specific ever, it is not authorised for use against secondary-progressive MS due to regional brain atrophy (Yu et al., 2020). In AD, there has been sub- lack of efficacy (Kapoor et al., 2018), implying a primary function in stantial assessment of CAMs (ICAM-1 and VCAM-1) in the plasma and preventing neurological damage following initial neuroinflammatory CSF (reviewed by Custodia et al., 2023), that appear to correlate with events. rapid progression of cognitive impairment (Drake et al., 2021). Post-mortem tissue from ischemic stroke patients (collected between 5 M. Ritson et al. Journal of Neuroimmunology 391 (2024) 578363 15 h and 18 days post-stroke), exhibits a substantial increase in cerebral risk factor for NDDs (Li et al., 2015; Verdile et al., 2015). Insulin sig- endothelial ICAM-1 expression (Lindsberg et al., 1996). The role of nalling is imperative for optimal cerebral EC and neuronal function ICAM-1 in neurodegeneration following stroke is supported by a rodent (Rhea and Banks, 2019). Decreased expression of insulin receptors in the study using a middle cerebral artery occlusion (MCAO) model of stroke, brain microvasculature of mice in vivo alters insulin signalling within the where treatment with an anti-ICAM-1 antibody significantly reduced brain (Konishi et al., 2017). Disruption to insulin signalling is common brain damage and the presence of leukocytes within lesions (Zhang to both diabetes and AD pathology (Arnold et al., 2018). In addition, et al., 1994). However, it should be noted that ICAM-1 is also expressed hyperglycaemia-induced production of compounds such as methyl- by some immune cells (macrophages and lymphocytes) so ICAM-1 in- glyoxal, a harmful oxoaldehyde, exacerbate endothelial dysfunction due hibition, unless targeted to ECs alone, will also affect these cell types. to increased cellular apoptosis and oxidative stress, therefore increasing Elevated ICAM-1 concentrations have also been reported in the sera of the risk of PD (Sabari et al., 2023). A murine model of type 2 diabetes acute ischemic stroke patients and associate with poor prognosis (Wang has shown extensive damage to BBB structure, occurring due to the et al., 2021). Despite these data, reducing CAM activation is not uni- increased presence of pro-inflammatory mediators and an altered im - versally protective. A clinical trial evaluating the treatment of ischemic mune response (Sheikh et al., 2022). The in vitro and in vivo models of stroke patients with Enimomab, an anti-ICAM-1 therapy, showed that type-2 diabetes studies in the work of Sheikh et al. (2022) both show a treatment led to more adverse events and a higher chance of death loss of tight junction protein expression and an increased influx of (Enlimomab Acute Stroke Trial, 2001). This variance is likely due, at neutrophils into the brain parenchyma (Li et al., 2022). These effects least in part, to the limitations of the real-world clinical environment, were reversed by either pharmacological intervention with recombinant where treatment is not given immediately after stroke (delayed until as ANXA1 (a mediator of glucocorticoid anti-inflammatory mechanisms, late as 6 h post stroke onset in this example); earlier initiation of known to reduce BBB leakage) or dietary reversion of the diabetes treatment may have led to a different outcome. Delayed treatment of phenotype (Sheikh et al., 2022). If early stages of metabolic disease, mice with anti-VCAM-1 in a model of ischemia-induced vascular de- such as diabetes, can cause systemic inflammation and BBB damage, mentia found significant reductions in neuroinflammation and cognitive then it is possible that undiagnosed or poorly controlled diabetes may decline, although early intervention with anti-VCAM-1 did not produce results in prolonged injury to the brain. This chronic systemic challenge the same effects (Zera et al., 2021). Together, these data indicate a time- to the cerebrovasculature may also have other actions to increase risk to dependence in the use of CAMs as a therapeutic target. Furthermore, no cerebral disease (see below) and warrant further investigation. protection against ischemic stroke, nor a difference in accumulation of Studies utilising animal models of chronic systemic inflammation inflammatory cells was found when the MCAO model was applied to have reported increased cognitive impairment and enhanced expression null transgenic ICAM-1 deficient mice (Enzmann et al., 2018), suggesting of dementia-associated risk factors (Sy et al., 2011; Marottoli et al., the existence of a more complex relationship between adhesion mole- 2017). The effect of systemic inflammation on the BBB has been cules, leukocyte infiltration and injury severity than is currently modelled in mice using peripheral injections of LPS (Nonaka et al., 2005; recognised. Qin et al., 2007; Franciosi et al., 2012; Banks et al., 2015; Zhao et al., 2019). There is evidence that neuroinflammation can significantly alter multiple BBB transport systems, such as those for insulin, TNF and 7. Can systemic disease push endothelial cells to dysfunction and affect the incidence, severity or onset of neurodegenerative amyloid beta peptide, and that these changes are further exaggerated with repeated exposure to LPS in vivo as opposed to a single high-dose disorders? LPS exposure (Xaio et al., 2001; Pan et al., 2008; Jaeger et al., 2009). In a transgenic animal model of AD, repeated low-medium dose LPS The association between chronic systemic inflammation and vascular disease is one that has been well documented (Petek et al., administration (0.5 mg/kg) over a 2-month period produced significant cerebrovascular injury, including increased vessel leakage and protein 2022). Findings from studies using models of NDDs alongside clinical data suggest that ongoing systemic inflammation may also exacerbate deposition in the parenchyma, alongside cognitive deficits (Marottoli et al., 2017). More work is required to understand the links between the occurrence and progression of neurological disorders via actions on the cerebrovasculature. This may occur via a number of mechanisms systemic inflammation and subsequent neurodegeneration, including the level of plasticity and repair possible within the cerebrovasculature, (some of which are discussed below), but more epidemiological studies how early irreparable vascular damage occurs, and the role of molecular are required to understand how systemic disease affects an individuals’ priming of endothelial inflammatory response as a contributor to the risk burden for neurological disease. Specifically, it is not yet clear severity of later injury. Processes of tolerance and sensitisation are whether systemic disease has a contribution of sufficient magnitude to increase the number of people who may later develop a neurodegener- known to affect inflammatory signalling following repetitive exposure (Gillen et al., 2021; Nürnberger et al., 2021; De Zuani et al., 2022; Li ative condition, or whether it interacts with other risk factors to affect the severity and/or timing of disease onset. et al., 2023). Which of these, if any, occur in cerebral ECs following repetitive or chronic (peripheral or central) inflammation has not yet One mechanism by which inflammation may lead to cerebrovascular dysfunction and NDDs is through the production of ROS, leading to a been established, but the outcomes of such studies will be critical for understanding mechanisms of endothelial dysfunction and whether el- state of oxidative stress (Song et al., 2020). Systemic oxidative stress has been associated with reduced ocular hemodynamic flow, linked to ements of the endothelial signalling pathways referenced above are potential candidates for effective therapeutic targeting. increased vascular permeability in patients with glaucoma (Himori et al., 2015). Neurodegeneration in NDD mouse models and patients, is As an additional factor, aging also affects the immune response and the cerebral vasculature (Malaguarnera et al., 2001). Aging is accom- associated with changes in oxidative stress and mitochondrial dysfunc- panied by an increase in cellular senescence, where cells undergoing tion (Henchcliffe and Beal, 2008; Elstner et al., 2011; Grammas et al., senescence release pro-inflammatory cytokines, promoting a chronic 2011; Reeve et al., 2013; Chang and Chen, 2020; Ahn et al., 2023). inflammatory state (Childs et al., 2015). Increasing proportions of se- Similarly, oxidative stress in ischemic stroke it has been proposed to heighten neuroinflammation through release of ROS, increasing pro - nescent cells appears to be a driving force in the progression of age- associated disorders which include atherosclerosis and NDDs (Saez- grammed cell death following ischemic injury. Although the molecular mechanisms behind this interplay are not known (reviewed by Wu et al., Atienzar and Masliah, 2020; Wissler Gerdes et al., 2020). Yamazaki et al. (2016) using an in vitro BBB model comprised of senescent primary cells, 2020). There is an accumulation of evidence linking diabetes, a primary highlighted an exacerbation of senescence in ECs, leading to decreased tight junction coverage and increased BBB disruption (Yamazaki et al., metabolic disorder, to cerebrovascular and cognitive disorders. Diabetes is characterised by dysregulated insulin signalling and is a recognised 2016). Additionally, in a senescence prone mouse model, it was found 6 M. Ritson et al. Journal of Neuroimmunology 391 (2024) 578363 that altered CBF arising from aging and vascular insult, correlated with a Acknowledgements decline in cognitive dysfunction (Zhang et al., 2013).Therefore the as- sociation between EC senescence, cerebrovascular inflammation, and None. increased BBB permeability is one that is well-established and requires further exploration in the context of early-life systemic disease and the References subsequent risk burden for NDDs (Graves and Baker, 2020; Han and Ahmad, A., Patel, V., Xiao, J., Khan, M.M., 2020. The role of neurovascular system in Kim, 2023). neurodegenerative diseases. Mol. Neurobiol. 57 (11), 4373–4393. Given the interplay between systemic inflammatory disease, acute Ahn, J.H., Kang, M.C., Lee, D., Cho, J.W., Park, K.A., Youn, J., 2023. 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The Lancet – Unpaywall

Published: Aug 1, 2011

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