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Intraneuronal aggregation of the β-CTF fragment of APP (C99) induces Aβ-independent lysosomal-autophagic pathology.
Acta Neuropathol. 2016 08; 132(2):257-276.AN

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+Show Affiliations

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.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.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.CCMA-Université de Nice-Sophia-Antipolis, Nice, France.Institut-Myologie, Paris, France.Institut-Myologie, Paris, France.Department of Neurobiology, Northwestern University, Evanston, IL, USA.Department of Neurobiology, Northwestern University, Evanston, IL, USA.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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27138984

Citation

Lauritzen, Inger, et al. "Intraneuronal Aggregation of the β-CTF Fragment of APP (C99) Induces Aβ-independent Lysosomal-autophagic Pathology." Acta Neuropathologica, vol. 132, no. 2, 2016, pp. 257-276.
Lauritzen I, Pardossi-Piquard R, Bourgeois A, et al. Intraneuronal aggregation of the β-CTF fragment of APP (C99) induces Aβ-independent lysosomal-autophagic pathology. Acta Neuropathol. 2016;132(2):257-276.
Lauritzen, I., Pardossi-Piquard, R., Bourgeois, A., Pagnotta, S., Biferi, M. G., Barkats, M., Lacor, P., Klein, W., Bauer, C., & Checler, F. (2016). Intraneuronal aggregation of the β-CTF fragment of APP (C99) induces Aβ-independent lysosomal-autophagic pathology. Acta Neuropathologica, 132(2), 257-276. https://doi.org/10.1007/s00401-016-1577-6
Lauritzen I, et al. Intraneuronal Aggregation of the β-CTF Fragment of APP (C99) Induces Aβ-independent Lysosomal-autophagic Pathology. Acta Neuropathol. 2016;132(2):257-276. PubMed PMID: 27138984.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Intraneuronal aggregation of the β-CTF fragment of APP (C99) induces Aβ-independent lysosomal-autophagic pathology. AU - Lauritzen,Inger, AU - Pardossi-Piquard,Raphaëlle, AU - Bourgeois,Alexandre, AU - Pagnotta,Sophie, AU - Biferi,Maria-Grazia, AU - Barkats,Martine, AU - Lacor,Pascale, AU - Klein,William, AU - Bauer,Charlotte, AU - Checler,Frederic, Y1 - 2016/04/30/ PY - 2015/12/08/received PY - 2016/04/22/accepted PY - 2016/04/21/revised PY - 2016/5/4/entrez PY - 2016/5/4/pubmed PY - 2017/9/1/medline KW - Aggregation KW - Alzheimer KW - Autophagy KW - C99 KW - Lysosomes KW - Triple-transgenic mouse KW - γ-Secretase inhibition SP - 257 EP - 276 JF - Acta neuropathologica JO - Acta Neuropathol VL - 132 IS - 2 N2 - 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. SN - 1432-0533 UR - https://www.unboundmedicine.com/medline/citation/27138984/Intraneuronal_aggregation_of_the_β_CTF_fragment_of_APP__C99__induces_Aβ_independent_lysosomal_autophagic_pathology_ L2 - https://dx.doi.org/10.1007/s00401-016-1577-6 DB - PRIME DP - Unbound Medicine ER -