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Alzheimer's Aβ(1–42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells

Alzheimer's Aβ(1–42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N... Alzheimer's disease (AD) is a neurodegenerative disorder involving the florid deposition of vascular and cerebral plaques composed chiefly of amyloid β-peptide (Aβ) derived from cleavage of the amyloid precursor protein (APP)1–2. Varying in length from 39 to 43 amino acids, Aβ, particularly the longer Aβ(42), is thought to play a significant role in AD pathogenesis3–4. To better understand AD it is important to identify the subcellular organelles generating Aβ. Studies using agents that disrupt endosomal/lysosomal function suggest that Aβ is generated late in the secretory and endocytic pathways5. However, much of what is known about Aβ biosynthesis has been inferred by monitoring extracellular Aβ levels since intracellular Aβ is undetectable in most cell types. Consequently, the precise site or sites that generate Aβ, or whether Aβ(1–40) and Aβ(1–42) are generated at the same point in the biosynthetic pathway, is not known. Using human NT2N neurons, we found that retention of APP in the endoplasmic reticulum/intermediate compartment (ER/IC) by three independent approaches eliminated production of intracellular Aβ(1–40), but did not alter intracellular Aβ(1–42) synthesis. These findings suggest that the ER/IC may be an important site for generating this highly amyloidogenic species of Aβ. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Medicine Springer Journals

Alzheimer's Aβ(1–42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells

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References (21)

Publisher
Springer Journals
Copyright
Copyright © 1997 by Nature Publishing Group
Subject
Biomedicine; Biomedicine, general; Cancer Research; Metabolic Diseases; Infectious Diseases; Molecular Medicine; Neurosciences
ISSN
1078-8956
eISSN
1546-170X
DOI
10.1038/nm0997-1021
Publisher site
See Article on Publisher Site

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder involving the florid deposition of vascular and cerebral plaques composed chiefly of amyloid β-peptide (Aβ) derived from cleavage of the amyloid precursor protein (APP)1–2. Varying in length from 39 to 43 amino acids, Aβ, particularly the longer Aβ(42), is thought to play a significant role in AD pathogenesis3–4. To better understand AD it is important to identify the subcellular organelles generating Aβ. Studies using agents that disrupt endosomal/lysosomal function suggest that Aβ is generated late in the secretory and endocytic pathways5. However, much of what is known about Aβ biosynthesis has been inferred by monitoring extracellular Aβ levels since intracellular Aβ is undetectable in most cell types. Consequently, the precise site or sites that generate Aβ, or whether Aβ(1–40) and Aβ(1–42) are generated at the same point in the biosynthetic pathway, is not known. Using human NT2N neurons, we found that retention of APP in the endoplasmic reticulum/intermediate compartment (ER/IC) by three independent approaches eliminated production of intracellular Aβ(1–40), but did not alter intracellular Aβ(1–42) synthesis. These findings suggest that the ER/IC may be an important site for generating this highly amyloidogenic species of Aβ.

Journal

Nature Medicine – Springer Journals

Published: Sep 1, 1997

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