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Acta Neuropathologica
Published in: Acta Neuropathologica 2/2016

Open Access 01-08-2016 | Original Paper

Intraneuronal aggregation of the β-CTF fragment of APP (C99) induces Aβ-independent lysosomal-autophagic pathology

Authors: Inger Lauritzen, Raphaëlle Pardossi-Piquard, Alexandre Bourgeois, Sophie Pagnotta, Maria-Grazia Biferi, Martine Barkats, Pascale Lacor, William Klein, Charlotte Bauer, Frederic Checler

Published in: Acta Neuropathologica | Issue 2/2016

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Abstract

Endosomal-autophagic-lysosomal (EAL) dysfunction is an early and prominent neuropathological feature of Alzheimers’s disease, yet the exact molecular mechanisms contributing to this pathology remain undefined. By combined biochemical, immunohistochemical and ultrastructural approaches, we demonstrate a link between EAL pathology and the intraneuronal accumulation of the β-secretase-derived βAPP fragment (C99) in two in vivo models, 3xTgAD mice and adeno-associated viral-mediated C99-infected mice. We present a pathological loop in which the accumulation of C99 is both the effect and causality of impaired lysosomal-autophagic function. The deleterious effect of C99 was found to be linked to its aggregation within EAL-vesicle membranes leading to disrupted lysosomal proteolysis and autophagic impairment. This effect was Aβ independent and was even exacerbated when γ-secretase was pharmacologically inhibited. No effect was observed in inhibitor-treated wild-type animals suggesting that lysosomal dysfunction was indeed directly linked to C99 accumulation. In some brain areas, strong C99 expression also led to inflammatory responses and synaptic dysfunction. Taken together, this work demonstrates a toxic effect of C99 which could underlie some of the early-stage anatomical hallmarks of Alzheimer’s disease pathology. Our work also proposes molecular mechanisms likely explaining some of the unfavorable side-effects associated with γ-secretase inhibitor-directed therapies.
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Metadata
Title
Intraneuronal aggregation of the β-CTF fragment of APP (C99) induces Aβ-independent lysosomal-autophagic pathology
Authors
Inger Lauritzen
Raphaëlle Pardossi-Piquard
Alexandre Bourgeois
Sophie Pagnotta
Maria-Grazia Biferi
Martine Barkats
Pascale Lacor
William Klein
Charlotte Bauer
Frederic Checler
Publication date
01-08-2016
Publisher
Springer Berlin Heidelberg
Published in
Acta Neuropathologica / Issue 2/2016
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-016-1577-6

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