Journal of Neurochemistry

doi: 10.1111/jnc.15629pmid: N/A

Bryson, Alexander; Reid, Christopher; Petrou, Steven

doi: 10.1111/jnc.15769pmid: 36681890

Epilepsy is a common neurological disorder associated with alterations of excitation‐inhibition balance within brain neuronal networks. GABAA receptor neurotransmission is the most prevalent form of inhibitory neurotransmission and is strongly implicated in both the pathophysiology and treatment of epilepsy, serving as a primary target for antiseizure medications for over a century. It is now established that GABA exerts a multifaceted influence through an array of GABAA receptor subtypes that extends far beyond simply negating excitatory activity. As the role of GABAA neurotransmission within inhibitory circuits is elaborated, this will enable the development of precision therapies that correct the network dysfunction underlying epileptic pathology.

Hernandez‐Espinosa, Diego R.; Gale, Jenna R.; Scrabis, Mia G.; Aizenman, Elias

doi: 10.1111/jnc.15760pmid: 36625847

Although the precise mechanisms determining the neurotoxic or neuroprotective activation phenotypes in microglia remain poorly characterized, metabolic changes in these cells appear critical for these processes. As cellular metabolism can be tightly regulated by changes in intracellular pH, we tested whether pharmacological targeting of the microglial voltage‐gated proton channel 1 (Hv1), an important regulator of intracellular pH, is critical for activated microglial reprogramming. Using a mouse microglial cell line and mouse primary microglia cultures, either alone, or co‐cultured with rat cerebrocortical neurons, we characterized in detail the microglial activation profile in the absence and presence of Hv1 inhibition. We observed that activated microglia neurotoxicity was mainly attributable to the release of tumor necrosis factor alpha, reactive oxygen species, and zinc. Strikingly, pharmacological inhibition of Hv1 largely abrogated inflammatory neurotoxicity not only by reducing the production of cytotoxic mediators but also by promoting neurotrophic molecule production and restraining excessive phagocytic activity. Importantly, the Hv1‐sensitive change from a pro‐inflammatory to a neuroprotective phenotype was associated with metabolic reprogramming, particularly via a boost in NADH availability and a reduction in lactate. Most critically, Hv1 antagonism not only reduced inflammatory neurotoxicity but also promoted microglia‐dependent neuroprotection against a separate excitotoxic injury. Our results strongly suggest that Hv1 blockers may provide an important therapeutic tool against a wide range of inflammatory neurodegenerative disorders.

Mok, Kingston King‐Shi; Yeung, Sunny Hoi‐Sang; Cheng, Gerald Wai‐Yeung; Ma, Iris Wai‐Ting; Lee, Ralph Hon‐Sun; Herrup, Karl; Tse, Kai‐Hei

doi: 10.1111/jnc.15748pmid: 36549843

Carriers of the APOE4 (apolipoprotein E ε4) variant of the APOE gene are subject to several age‐related health risks, including Alzheimer's disease (AD). The deficient lipid and cholesterol transport capabilities of the APOE4 protein are one reason for the altered risk profile. In particular, APOE4 carriers are at elevated risk for sporadic AD. While deposits o misfolded proteins are present in the AD brain, white matter (WM) myelin is also disturbed. As myelin is a lipid‐ and cholesterol‐rich structure, the connection to APOE makes considerable biological sense. To explore the APOE‐WM connection, we have analyzed the impact of human APOE4 on oligodendrocytes (OLs) of the mouse both in vivo and in vitro. We find that APOE proteins is enriched in astrocytes but sparse in OL. In human APOE4 (hAPOE4) knock‐in mice, myelin lipid content is increased but the density of major myelin proteins (MBP, MAG, and PLP) is largely unchanged. We also find an unexpected but significant reduction of cell density of the OL lineage (Olig2+) and an abnormal accumulation of OL precursors (Nkx 2.2+), suggesting a disruption of OL differentiation. Gene ontology analysis of an existing RNA‐seq dataset confirms a robust transcriptional response to the altered chemistry of the hAPOE4 mouse brain. In culture, the uptake of astrocyte‐derived APOE during Lovastatin‐mediated depletion of cholesterol synthesis is sufficient to sustain OL differentiation. While endogenous hAPOE protein isoforms have no effects on OL development, exogenous hAPOE4 abolishes the ability of very low‐density lipoprotein to restore myelination in Apoe‐deficient, cholesterol‐depleted OL. Our data suggest that APOE4 impairs myelination in the aging brain by interrupting the delivery of astrocyte‐derived lipids to the oligodendrocytes. We propose that high myelin turnover and OL exhaustion found in APOE4 carriers is a likely explanation for the APOE‐dependent myelin phenotypes of the AD brain.

Villadsen, Birgitte; Thygesen, Camilla; Grebing, Manuela; Kempf, Stefan J.; Sandberg, Marie B.; Jensen, Pia; Kolstrup, Stefanie H.; Nielsen, Helle H.; Larsen, Martin R.; Finsen, Bente

doi: 10.1111/jnc.15754pmid: 36583241

Ceruloplasmin (Cp) is a multicopper oxidase with ferroxidase properties being of importance to the mobilisation and export of iron from cells and its ability to bind copper. In ageing humans, Cp deficiency is known to result in aceruloplasminemia, which among other is characterised by neurological symptoms. To obtain novel information about the functions of Cp in the central nervous system (CNS) we compared the brain proteome in forebrains from asymptomatic 4‐6‐month‐old Cp‐deficient (B6N(Cg)‐Cptm1b(KOMP)Wtsi/J) and wild‐type mice. Of more than 5600 quantified proteins, 23 proteins, were regulated, whereas more than 1200 proteins had regulated post‐translational modifications (PTMs). The genes of the regulated proteins, glycoproteins and phosphoproteins appeared mostly to be located to neurons and oligodendrocyte precursor cells. Cp deficiency especially affected the function of proteins involved in the extension of neuronal projections, synaptic signalling and cellular mRNA processing and affected the expression of proteins involved in neurodegenerative disease and diabetes. Iron concentration and transferrin saturation were reduced in the blood of even younger, 3‐ to 5‐month‐old, Cp‐deficient mice. Iron act as cofactor in many enzymatic processes and reactions. Changes in iron availability and oxidation as consequence of Cp deficiency could therefore affect the synthesis of proteins and lipids. This proteomic characterisation is to our knowledge the first to document the changes taking place in the CNS‐proteome and its phosphorylation and glycosylation state in Cp‐deficient mice.

Kurz, Carolin; Stöckl, Laura; Schrurs, Isabelle; Suridjan, Ivonne; Gürsel, Selim Üstün; Bittner, Tobias; Jethwa, Alexander; Perneczky, Robert

doi: 10.1111/jnc.15757pmid: 36625424

An unmet need exists for reliable plasma biomarkers of amyloid pathology, in the clinical laboratory setting, to streamline diagnosis of Alzheimer's disease (AD). For routine clinical use, a biomarker must provide robust and reliable results under pre‐analytical sample handling conditions. We investigated the impact of different pre‐analytical sample handling procedures on the levels of seven plasma biomarkers in development for potential routine use in AD. Using (1) fresh (never frozen) and (2) previously frozen plasma, we evaluated the effects of (A) storage time and temperature, (B) freeze/thaw (F/T) cycles, (C) anticoagulants, (D) tube transfer, and (E) plastic tube types. Blood samples were prospectively collected from patients with cognitive impairment undergoing investigation in a memory clinic. β‐amyloid 1–40 (Aβ40), β‐amyloid 1–42 (Aβ42), apolipoprotein E4, glial fibrillary acidic protein, neurofilament light chain, phosphorylated‐tau (phospho‐tau) 181, and phospho‐tau‐217 were measured using Elecsys® plasma prototype immunoassays. Recovery signals for each plasma biomarker and sample handling parameter were calculated. For all plasma biomarkers measured, pre‐analytical effects were comparable between fresh (never frozen) and previously frozen samples. All plasma biomarkers tested were stable for ≤24 h at 4°C when stored as whole blood and ethylenediaminetetraacetic acid (EDTA) plasma. Recovery signals were acceptable for up to five tube transfers, or two F/T cycles, and in both polypropylene and low‐density polyethylene tubes. For all plasma biomarkers except Aβ42 and Aβ40, analyte levels were largely comparable between EDTA, lithium heparin, and sodium citrate tubes. Aβ42 and Aβ40 were most sensitive to pre‐analytical handling, and the effects could only be partially compensated by the Aβ42/Aβ40 ratio. We provide recommendations for an optimal sample handling protocol for analysis of plasma biomarkers for amyloid pathology AD, to improve the reproducibility of future studies on plasma biomarkers assays and for potential use in routine clinical practice.

doi: 10.1111/jnc.15791pmid: 36883226

The above article, published online on 28th July 2006 in Wiley Online Library (wileyonlinelibrary.com), is retracted by agreement between the authors (with the exception of Brian T. Larsen who could not be reached), the journal's Editor in Chief, Andrew Lawrence, and John Wiley & Sons Ltd. The retraction has been agreed due to concerns raised regarding possible image manipulation of Figure 1c and e, Figure 3c, Figure 4c (i), Figure 4c (iii), Figure 5a‐b and 5c. The authors were unable to provide the original datasets upon request. Therefore, the data and the conclusions of the manuscript can no longer be considered reliable. The authors acknowledge and regret these mistakes.