期刊
ACTA NEUROPATHOLOGICA
卷 131, 期 2, 页码 247-266出版社
SPRINGER
DOI: 10.1007/s00401-015-1498-9
关键词
Alzheimer; Gene therapy; Amyloid precursor protein; APPs alpha; Synaptic plasticity; Spines; Behavior; Microglia; AAV
资金
- Deutsche Forschungsgemeinschaft [MU 1457/9-1, MU 1457/9-2, KO 1674/3-1, KO 1674/3-2]
- ERA-Net Neuron [01EW1305A]
- LOEWE Center for Cell and Gene Therapy Frankfurt - Hessisches Ministerium fur Wissenschaft und Kunst [III L 4-518/17.004 (2010)]
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 beta-amyloid accumulation and plaque deposition. However, increasing evidence indicates that loss of physiological APP functions mediated predominantly by neurotrophic APPs alpha produced in the non-amyloidogenic alpha-secretase pathway may contribute to AD pathogenesis. Upregulation of APPs alpha production via induction of alpha-secretase might, however, be problematic as this may also affect substrates implicated in tumorigenesis. Here, we used a gene therapy approach to directly overexpress APPs alpha in the brain using AAV-mediated gene transfer and explored its potential to rescue structural, electrophysiological and behavioral deficits in APP/PS1a dagger E9 AD model mice. Sustained APPs alpha overexpression in aged mice with already preexisting pathology and amyloidosis restored synaptic plasticity and partially rescued spine density deficits. Importantly, AAV-APPs alpha treatment also resulted in a functional rescue of spatial reference memory in the Morris water maze. Moreover, we demonstrate a significant reduction of soluble A beta species and plaque load. In addition, APPs alpha 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 APPs alpha can mitigate synaptic and cognitive deficits, despite established pathology. Increasing APPs alpha may therefore be of therapeutic relevance for AD.
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