SPIN90 deficiency ameliorates Amyloid β accumulation by Rab11 related APP trafficking in 5xFAD mice

Abstract

Alzheimer’ disease (AD), common form of dementia, is caused in part by the aggregation and accumulation in the brain of amyloid β (Aβ), a product of the proteolytic cleavage of amyloid precursor protein (APP) in endosome. Trafficking of APP, such as surfaceintracellular trafficking, is an early critical step required for Aβ generation. Less is known, however, about the molecular mechanism regulating APP trafficking. This study investigated the mechanism by which SPIN90, along with Rab11, modulates APP trafficking, Aβ motility and accumulation, and synaptic functionality. Brain Aβ deposition was lower in the progeny of 5xFAD-SPIN90 KO mice than in 5xFAD-SPIN90 WT mice. Analysis of APP distribution and trafficking showed that the surface fraction of APP was locally distinct in axons and dendrites, with these distributions differing significantly in 5xFAD-SPIN90 WT and 5xFADSPIN90 KO mice, and that neural activity-driven APP trafficking to the surface and intracellular recycling were more actively mobilized in 5xFAD-SPIN90 KO neurons. In addition, SPIN90 was found to be cotrafficked with APP via axons, with ablation of SPIN90 reducing the intracellular accumulation of APP in axons. Finally, synaptic transmission was restored over time in 5xFAD-SPIN90 KO but not in 5xFAD-SPIN90 WT neurons, suggesting SPIN90 is implicated in Aβ production through the regulation of Rab11 related APP trafficking.