59. APPsα Gene Therapy for Alzheimer's Disease

Alzheimeru0027s disease (AD) is characterized by synaptic failure, dendritic and axonal atrophy, neuronal death and progressive loss of cognitive functions asocieted with β-amyloid accumulation and neurofibrillary tangles of phosphorylated Tau protein. 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. We used an AAV vector to directly overexpress APPsa in the brain and explored its potential to rescue structural, electrophysiological and behavioral deficits in APP/PS1ΔE9 AD mouse model. Sustained APPsα overexpression in aged mice with already preexisting pathology and amyloidosis restored synaptic plasticity and rescued spine density deficits. Importantly, AAV-APPsα treatment also resulted in a functional rescue of spatial memory. A significant reduction of both toxic soluble β42 and plaque load was evidenced. APPsα induced the recruitment of microglia with ramified morphology towards plaques and upregulated IDE and TREM2 expression suggesting enhanced plaque clearance. APPsα overexpression in the brain using an AAV vector improves synaptic and cognitive deficits, despite established pathology and may be of therapeutic relevance for AD.