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.
Original language | English (US) |
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Pages (from-to) | 257-276 |
Number of pages | 20 |
Journal | Acta Neuropathologica |
Volume | 132 |
Issue number | 2 |
DOIs | |
State | Published - Aug 1 2016 |
Funding
We wish to thank Dr. Laferla for providing the 3xTgAD mouse, Elan Pharmaceuticals for ELND006, Dr Gan and Dr Zhou for giving the cathepsin B lentivirus and Dr Fraser for the APPct antibody. We also thank Mathilde Cohen-Tannoudji for help in producing AAVs. This work has been developed and supported through the LABEX (excellence laboratory, program investment for the future) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease and the University hospital Federation (FHU) OncoAge. This work was supported by “Conseil Départemantal des Alpes Maritimes”. The authors declare no competing financial interests. We wish to thank Dr. Laferla for providing the 3xTgAD mouse, Elan Pharmaceuticals for ELND006, Dr Gan and Dr Zhou for giving the cathepsin B lentivirus and Dr Fraser for the APPct antibody. We also thank Mathilde Cohen-Tannoudji for help in producing AAVs. This work has been developed and supported through the LABEX (excellence laboratory, program investment for the future) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease and the University hospital Federation (FHU) OncoAge. This work was supported by “Conseil Départemantal des Alpes Maritimes”.
Keywords
- Aggregation
- Alzheimer
- Autophagy
- C99
- Lysosomes
- Triple-transgenic mouse
- γ-Secretase inhibition
ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Clinical Neurology
- Cellular and Molecular Neuroscience