Viral gene transfer of APPsα rescues synaptic failure in an Alzheimer’s disease mouse model

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ID: 119748
2015
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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.
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fol2015actaviral Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Romain Fol;Jerome Braudeau;Susann Ludewig;Tobias Abel;Sascha W. Weyer;Jan-Peter Roederer;Florian Brod;Mickael Audrain;Alexis-Pierre Bemelmans;Christian J. Buchholz;Martin Korte;Nathalie Cartier;Ulrike C. Müller;Romain Fol;Jerome Braudeau;Susann Ludewig;Tobias Abel;Sascha W. Weyer;Jan-Peter Roederer;Florian Brod;Mickael Audrain;Alexis-Pierre Bemelmans;Christian J. Buchholz;Martin Korte;Nathalie Cartier;Ulrike C. Müller;
Journal acta neuropathologica
Year 2015
DOI
doi:10.1007/s00401-015-1498-9
URL
https://link.springer.com/article/10.1007/s00401-015-1498-9
Keywords
pathology neurosciences

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