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PMID: 12414533 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology.

The American journal of pathology ·Vol. 161 ·No. 5 ·2002-11-00 ·Pages 1869-79

Takahashi RH, Milner TA, Li F, Nam EE, Edgar MA, Yamaguchi H, Beal MF, Xu H, Greengard P, Gouras GK

Abstract

A central question in Alzheimer's disease concerns the mechanism by which beta-amyloid contributes to neuropathology, and in particular whether intracellular versus extracellular beta-amyloid plays a critical role. Alzheimer transgenic mouse studies demonstrate brain dysfunction, as beta-amyloid levels rise, months before the appearance of beta-amyloid plaques. We have now used immunoelectron microscopy to determine the subcellular site of neuronal beta-amyloid in normal and Alzheimer brains, and in brains from Alzheimer transgenic mice. We report that beta-amyloid 42 localized predominantly to multivesicular bodies of neurons in normal mouse, rat, and human brain. In transgenic mice and human Alzheimer brain, intraneuronal beta-amyloid 42 increased with aging and beta-amyloid 42 accumulated in multivesicular bodies within presynaptic and especially postsynaptic compartments. This accumulation was associated with abnormal synaptic morphology, before beta-amyloid plaque pathology, suggesting that intracellular accumulation of beta-amyloid plays a crucial role in Alzheimer's disease.

MeSH Terms
Aging Alzheimer Disease/metabolism,pathology Amyloid beta-Peptides/analysis,immunology Amyloid beta-Protein Precursor/genetics Animals Brain/cytology,ultrastructure Cytoplasmic Vesicles/chemistry,ultrastructure Humans Mice Mice, Knockout Mice, Transgenic Microscopy, Immunoelectron Middle Aged Neurons/chemistry,ultrastructure Peptide Fragments/analysis,immunology Rats Synapses/chemistry,ultrastructure
Chemicals
Amyloid beta-Peptides Amyloid beta-Protein Precursor Peptide Fragments amyloid beta-protein (1-42)
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Takahashi Reisuke H
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, USA.
Milner Teresa A
Li Feng
Nam Ellen E
Edgar Mark A
Yamaguchi Haruyasu
Beal M Flint
Xu Huaxi
Greengard Paul
Gouras Gunnar K
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Article Info
Journal
The American journal of pathology
Abbr.
Am J Pathol
ISSN
0002-9440
DOI
10.1016/s0002-9440(10)64463-x
Published
2002-11-00
Pages
1869-79
Language
English
Region
United States
NLM ID
0370502
PMCID
PMC1850783
Subset
IM
Grants
NHLBI NIH HHS · HL18974 · United States
NINDS NIH HHS · NS02037 · United States
NHLBI NIH HHS · P01 HL018974 · United States
NIA NIH HHS · P01 AG009464 · United States
NIA NIH HHS · AG09464 · United States
External Links
PubMed source DOI: 10.1016/s0002-9440(10)64463-x PMC Full Text View journal details
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