SPIN90 Deficiency Ameliorates Amyloid ß Accumulation by Regulating APP Trafficking in AD Model Mice

Abstract

AbstractBackgroundAlzheimer’s disease (AD), a common form of dementia, is caused in part by the aggregation and accumulation in the brain of amyloid ß (Aß), a product of the proteolytic cleavage of amyloid precursor protein (APP) in endosomes. Trafficking of APP, such as surface‐intracellular recycling, 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 functionalityMethodThis study utilized live‐imaging technology with molecular, cellular and 5xFAD model mice system.ResultBrain Aβ deposition was lower in the progeny of 5xFAD‐SPIN90KO mice than in 5xFAD‐SPIN90WT 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‐SPIN90WT and 5xFAD‐SPIN90KO mice, and that neural activity‐driven APP trafficking to the surface and intracellular recycling were more actively mobilized in 5xFAD‐SPIN90KO 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‐SPIN90KO but not in 5xFAD‐SPIN90WT neuronsConclusionThe interaction of SPIN90 and Rab11 is implicated in Aβ production through the regulation of APP trafficking.