Slingshot-Cofilin activation mediates mitochondrial and synaptic dysfunction via A beta ligation to beta 1-integrin conformers

摘要

The accumulation of amyloid-beta protein (A beta) is an early event associated with synaptic and mitochondrial damage in Alzheimer's disease (AD). Recent studies have implicated the filamentous actin (F-actin) severing protein, Cofilin, in synaptic remodeling, mitochondrial dysfunction, and AD pathogenesis. However, whether Cofilin is an essential component of the AD pathogenic process and how A beta impinges its signals to Cofilin from the neuronal surface are unknown. In this study, we found that A beta 42 oligomers (A beta 42(O), amyloid-beta protein 1-42 oligomers) bind with high affinity to low or intermediate activation conformers of beta 1-integrin, resulting in the loss of surface beta 1-integrin and activation of Cofilin via Slingshot homology-1 (SSH1) activation. Specifically, conditional loss of beta 1-integrin prevented A beta 42(O)-induced Cofilin activation, and allosteric modulation or activation of beta 1-integrin significantly reduced A beta 42(O) binding to neurons while blocking A beta 42(O)-induced reactive oxygen species (ROS) production, mitochondrial dysfunction, depletion of F-actin/focal Vinculin, and apoptosis. Cofilin, in turn, was required for A beta 42(O)-induced loss of cell surface beta 1-integrin, disruption of F-actin/focal Talin-Vinculin, and depletion of F-actin-associated postsynaptic proteins. SSH1 reduction, which mitigated Cofilin activation, prevented A beta 42(O)-induced mitochondrial Cofilin translocation and apoptosis, while AD brain mitochondria contained significantly increased activated/oxidized Cofilin. In mechanistic support in vivo, AD mouse model (APP (amyloid precursor protein)/PS1) brains contained increased SSH1/Cofilin and decreased SSH1/14-3-3 complexes, indicative of SSH1-Cofilin activation via release of SSH1 from 14-3-3. Finally, genetic reduction in Cofilin rescued APP/A beta-induced synaptic protein loss and gliosis in vivo as well as deficits in long-term potentiation (LTP) and contextual memory in APP/PS1 mice. These novel findings therefore implicate the essential involvement of the beta 1-integrin-SSH1-Cofilin pathway in mitochondrial and synaptic dysfunction in AD.