Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration

Alzheimer disease is a major cause of cognitive failure, and a pathogenically related but more subtle process accounts for many cases of mild memory symptoms in older humans. Insoluble fibrillar plaques of amyloid β-proteins (Aβ) and neurofibrillary deposits of hyperphosphorylated tau proteins are t...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 14; p. 5819
Main Authors: Jin, Ming, Shepardson, Nina, Yang, Ting, Chen, Gang, Walsh, Dominic, Selkoe, Dennis J
Format: Journal Article
Language:English
Published: United States 05.04.2011
Subjects:
Alzheimer Disease - physiopathology
Amyloid beta-Peptides - metabolism
Amyloid beta-Peptides - pharmacology
Animals
Blotting, Western
Chromatography, Gel
Dimerization
Genetic Vectors - genetics
Hippocampus - cytology
Humans
Immunohistochemistry
Immunoprecipitation
In Situ Nick-End Labeling
Lentivirus
Microscopy, Confocal
Microtubules - drug effects
Neurites - drug effects
Neurites - pathology
Phosphorylation - drug effects
Rats
Rats, Sprague-Dawley
tau Proteins - metabolism
ISSN:1091-6490, 1091-6490
Online Access:Get more information
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Alzheimer disease is a major cause of cognitive failure, and a pathogenically related but more subtle process accounts for many cases of mild memory symptoms in older humans. Insoluble fibrillar plaques of amyloid β-proteins (Aβ) and neurofibrillary deposits of hyperphosphorylated tau proteins are the diagnostic lesions of AD, but their temporal mechanistic relationship has long been debated. The recent recognition that small, diffusible oligomers may be the principal bioactive form of Aβ raises the key question of whether these are sufficient to initiate cytoskeletal change and neurite degeneration. A few studies have examined the effects of oligomers of synthetic Aβ peptides of one defined length at supraphysiological concentrations, but the existence of such assemblies in the AD brain is not established. Here, we isolated Aβ dimers, the most abundant form of soluble oligomer detectable in the human brain, from the cortices of typical AD subjects and found that at subnanomolar concentrations, they first induced hyperphosphorylation of tau at AD-relevant epitopes in hippocampal neurons and then disrupted the microtubule cytoskeleton and caused neuritic degeneration, all in the absence of amyloid fibrils. Application of pure, synthetic dimers confirmed the effects of the natural AD dimers, although the former were far less potent. Knocking down endogenous tau fully prevented the neuritic changes, whereas overexpressing human tau accelerated them. Coadministering Aβ N-terminal antibodies neutralized the cytoskeletal disruption. We conclude that natural dimers isolated from the AD brain are sufficient to potently induce AD-type tau phosphorylation and then neuritic dystrophy, but passive immunotherapy mitigates this.
Bibliography:ObjectType-Article-2
SourceType-Scholarly Journals-1
ObjectType-Feature-1
content type line 23
ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.1017033108