title: Viral gene transfer of APPsα rescues synaptic failure in an Alzheimer's disease mouse model.
abstract: Alzheimer's disease (AD) is characterized by synaptic failure, dendritic and axonal atrophy, neuronal death and progressive loss of cognitive functions. It is commonly assumed that these deficits arise due to β-amyloid accumulation and plaque deposition. However, increasing evidence indicates that loss of physiological APP functions mediated predominantly by neurotrophic APPsα produced in the non-amyloidogenic α-secretase pathway may contribute to AD pathogenesis. Upregulation of APPsα production via induction of α-secretase might, however, be problematic as this may also affect substrates implicated in tumorigenesis. Here, we used a gene therapy approach to directly overexpress APPsα in the brain using AAV-mediated gene transfer and explored its potential to rescue structural, electrophysiological and behavioral deficits in APP/PS1∆E9 AD model mice. Sustained APPsα overexpression in aged mice with already preexisting pathology and amyloidosis restored synaptic plasticity and partially rescued spine density deficits. Importantly, AAV-APPsα treatment also resulted in a functional rescue of spatial reference memory in the Morris water maze. Moreover, we demonstrate a significant reduction of soluble Aβ species and plaque load. In addition, APPsα induced the recruitment of microglia with a ramified morphology into the vicinity of plaques and upregulated IDE and TREM2 expression suggesting enhanced plaque clearance. Collectively, these data indicate that APPsα can mitigate synaptic and cognitive deficits, despite established pathology. Increasing APPsα may therefore be of therapeutic relevance for AD.
authors.affiliation: INSERM U1169/MIRCen CEA, 92265, Fontenay aux Roses, France.|University Paris Sud, University Paris-Saclay, 91400, Orsay, France.|Université Paris Descartes, 75006, Paris, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Fol
authors.affiliation: INSERM U1169/MIRCen CEA, 92265, Fontenay aux Roses, France.|University Paris Sud, University Paris-Saclay, 91400, Orsay, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Braudeau
authors.affiliation: Division of Cellular Neurobiology, Zoological Institute, TU Braunschweig, Brunswick, Germany.
authors.forename: Susann
authors.initials: S
authors.lastname: Ludewig
authors.affiliation: Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225, Langen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Abel
authors.affiliation: Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany.
authors.forename: Sascha W
authors.initials: SW
authors.lastname: Weyer
authors.affiliation: Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany.
authors.forename: Jan-Peter
authors.initials: JP
authors.lastname: Roederer
authors.affiliation: Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225, Langen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Brod
authors.affiliation: INSERM U1169/MIRCen CEA, 92265, Fontenay aux Roses, France.|University Paris Sud, University Paris-Saclay, 91400, Orsay, France.|Université Paris Descartes, 75006, Paris, France.
authors.forename: Mickael
authors.initials: M
authors.lastname: Audrain
authors.affiliation: University Paris Sud, University Paris-Saclay, 91400, Orsay, France.|Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), 92260, Fontenay aux Roses, France.|Centre National de la Recherche Scientifique (CNRS), UMR 9199, Neurodegenerative Diseases Laboratory, 92260, Fontenay aux Roses, France.
authors.forename: Alexis-Pierre
authors.initials: AP
authors.lastname: Bemelmans
authors.affiliation: Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225, Langen, Germany.
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Buchholz
authors.affiliation: Division of Cellular Neurobiology, Zoological Institute, TU Braunschweig, Brunswick, Germany.|Helmholtz Centre for Infection Research, AG NIND, Inhoffenstr. 7, 38124, Brunswick, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Korte
authors.affiliation: INSERM U1169/MIRCen CEA, 92265, Fontenay aux Roses, France. nathalie.cartier@inserm.fr.|University Paris Sud, University Paris-Saclay, 91400, Orsay, France. nathalie.cartier@inserm.fr.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cartier
authors.affiliation: Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany. u.mueller@urz.uni-heidelberg.de.
authors.forename: Ulrike C
authors.initials: UC
authors.lastname: Müller
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology / Q000502:physiology; D009474:Neurons / Q000473:pathology / Q000502:physiology; D058225:Plaque, Amyloid / Q000473:pathology / Q000503:physiopathology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000502:physiology*; D046509:Tissue Culture Techniques
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases
keywords: AAV; APPsα; Alzheimer; Amyloid precursor protein; Behavior; Gene therapy; Microglia; Spines; Synaptic plasticity