βAPP Processing Drives Gradual Tau Pathology in an Age-Dependent Amyloid Rat Model of Alzheimer's Disease.

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Version: author
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Serval ID
serval:BIB_33C08EF71CE9
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
βAPP Processing Drives Gradual Tau Pathology in an Age-Dependent Amyloid Rat Model of Alzheimer's Disease.
Journal
Cerebral cortex
Author(s)
Audrain M., Souchet B., Alves S., Fol R., Viode A., Haddjeri A., Tada S., Orefice N.S., Joséphine C., Bemelmans A.P., Delzescaux T., Déglon N., Hantraye P., Akwa Y., Becher F., Billard J.M., Potier B., Dutar P., Cartier N., Braudeau J.
ISSN
1460-2199 (Electronic)
ISSN-L
1047-3211
Publication state
Published
Issued date
01/11/2018
Peer-reviewed
Oui
Volume
28
Number
11
Pages
3976-3993
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
The treatment of Alzheimer's disease (AD) remains challenging and requires a better in depth understanding of AD progression. Particularly, the link between amyloid protein precursor (APP) processing and Tau pathology development remains poorly understood. Growing evidences suggest that APP processing and amyloid-β (Aβ) release are upstream of Tau pathology but the lack of animal models mimicking the slow progression of human AD raised questions around this mechanism. Here, we described that an AD-like βAPP processing in adults wild-type rats, yielding to human APP, βCTF and Aβ levels similar to those observed in AD patients, is sufficient to trigger gradual Tauopathy. The Tau hyperphosphorylation begins several months before the formation of both amyloid plaques and tangle-like aggregates in aged rats and without associated inflammation. Based on a longitudinal characterization over 30 months, we showed that extrasynaptic and emotional impairments appear before long-term potentiation deficits and memory decline and so before Aβ and Tau aggregations. These compelling data allowed us to (1) experimentally confirm the causal relationship between βAPP processing and Tau pathology in vivo and without Tau transgene overexpression, (2) support the amyloidogenic cascade and (3) propose a 4-step hypothesis of prodromal AD progression.
Keywords
Aged, Aged, 80 and over, Alzheimer Disease/metabolism, Amyloid beta-Peptides/metabolism, Amyloid beta-Protein Precursor/metabolism, Animals, Disease Models, Animal, Disease Progression, Female, Genetic Vectors, Hippocampus/metabolism, Hippocampus/pathology, Humans, Long-Term Potentiation, Male, Peptide Fragments/metabolism, Plaque, Amyloid/metabolism, Presenilin-1/genetics, Protein Aggregation, Pathological/metabolism, Rats, Wistar, tau Proteins/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
02/11/2017 15:06
Last modification date
19/06/2020 6:21
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