ABSTRACT: The accumulation of amyloid-? protein (A?) 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? impinges its signals to Cofilin from the neuronal surface are unknown. In this study, we found that A?42 oligomers (A?42O, amyloid-? protein 1-42 oligomers) bind with high affinity to low or intermediate activation conformers of ?1-integrin, resulting in the loss of surface ?1-integrin and activation of Cofilin via Slingshot homology-1 (SSH1) activation. Specifically, conditional loss of ?1-integrin prevented A?42O-induced Cofilin activation, and allosteric modulation or activation of ?1-integrin significantly reduced A?42O binding to neurons while blocking A?42O-induced reactive oxygen species (ROS) production, mitochondrial dysfunction, depletion of F-actin/focal Vinculin, and apoptosis. Cofilin, in turn, was required for A?42O-induced loss of cell surface ?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?42O-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?-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 ?1-integrin-SSH1-Cofilin pathway in mitochondrial and synaptic dysfunction in AD.
