title: Intraneuronal aggregation of the β-CTF fragment of APP (C99) induces Aβ-independent lysosomal-autophagic pathology.
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.
authors.affiliation: Université de Nice-Sophia-Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UMR7275, Team Labelised Fondation pour la Recherche Médicale et Laboratoire d'excellence Distalz, Sophia-Antipolis, France.
authors.forename: Inger
authors.initials: I
authors.lastname: Lauritzen
authors.affiliation: Université de Nice-Sophia-Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UMR7275, Team Labelised Fondation pour la Recherche Médicale et Laboratoire d'excellence Distalz, Sophia-Antipolis, France.
authors.forename: Raphaëlle
authors.initials: R
authors.lastname: Pardossi-Piquard
authors.affiliation: Université de Nice-Sophia-Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UMR7275, Team Labelised Fondation pour la Recherche Médicale et Laboratoire d'excellence Distalz, Sophia-Antipolis, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bourgeois
authors.affiliation: CCMA-Université de Nice-Sophia-Antipolis, Nice, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Pagnotta
authors.affiliation: Institut-Myologie, Paris, France.
authors.forename: Maria-Grazia
authors.initials: MG
authors.lastname: Biferi
authors.affiliation: Institut-Myologie, Paris, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Barkats
authors.affiliation: Department of Neurobiology, Northwestern University, Evanston, IL, USA.
authors.forename: Pascale
authors.initials: P
authors.lastname: Lacor
authors.affiliation: Department of Neurobiology, Northwestern University, Evanston, IL, USA.
authors.forename: William
authors.initials: W
authors.lastname: Klein
authors.affiliation: Université de Nice-Sophia-Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UMR7275, Team Labelised Fondation pour la Recherche Médicale et Laboratoire d'excellence Distalz, Sophia-Antipolis, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Bauer
authors.affiliation: Université de Nice-Sophia-Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UMR7275, Team Labelised Fondation pour la Recherche Médicale et Laboratoire d'excellence Distalz, Sophia-Antipolis, France. checler@ipmc.cnrs.fr.
authors.forename: Frederic
authors.initials: F
authors.lastname: Checler
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000502:physiology; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D011992:Endosomes / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism* / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases
keywords: Aggregation; Alzheimer; Autophagy; C99; Lysosomes; Triple-transgenic mouse; γ-Secretase inhibition