Full recovery of the Alzheimer's disease phenotype by gain of function of vacuolar protein sorting 35

Deficit in retromer complex function secondary to lower levels of one of its major components, the vacuolar protein sorting 35 (VPS35), has been reported in Alzheimer's disease (AD) brains. VPS35 genetic reduction results in increased A beta levels and synaptic pathology in mouse models of the disease. However, whether restoration of its levels has an effect on the AD-like phenotype which includes A beta plaques, tau tangles and memory impairments remain unknown. In this paper, we investigated the effect of VPS35 gene delivery into the central nervous system on the development of the neuropathology and behavioral deficits of the triple transgenic (3xTg) mice. Compared with controls, animals overexpressing VPS35 had an amelioration of spatial learning and working memory, which associated with a significant reduction in A beta levels and deposition and tau phosphorylation. Additionally, the same animals had a significant improvement of synaptic pathology and neuroinflammation. In vitro study confirmed that VPS35 up-regulation by reducing total levels of APP and results in a significant decrease in its metabolic products. Our results demonstrate for the first time that VPS35 is directly involved in the development of AD-like phenotype, and for this reason should be considered as a novel therapeutic target for AD.