| First Author | Woo JA | Year | 2015 |
| Journal | Cell Death Differ | Volume | 22 |
| Issue | 6 | Pages | 921-34 |
| PubMed ID | 25698445 | Mgi Jnum | J:247631 |
| Mgi Id | MGI:5922619 | Doi | 10.1038/cdd.2015.5 |
| Citation | Woo JA, et al. (2015) Slingshot-Cofilin activation mediates mitochondrial and synaptic dysfunction via Abeta ligation to beta1-integrin conformers. Cell Death Differ 22(6):921-34 |
| abstractText | The accumulation of amyloid-beta protein (Abeta) 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 Abeta impinges its signals to Cofilin from the neuronal surface are unknown. In this study, we found that Abeta42 oligomers (Abeta42O, amyloid-beta protein 1-42 oligomers) bind with high affinity to low or intermediate activation conformers of beta1-integrin, resulting in the loss of surface beta1-integrin and activation of Cofilin via Slingshot homology-1 (SSH1) activation. Specifically, conditional loss of beta1-integrin prevented Abeta42O-induced Cofilin activation, and allosteric modulation or activation of beta1-integrin significantly reduced Abeta42O binding to neurons while blocking Abeta42O-induced reactive oxygen species (ROS) production, mitochondrial dysfunction, depletion of F-actin/focal Vinculin, and apoptosis. Cofilin, in turn, was required for Abeta42O-induced loss of cell surface beta1-integrin, disruption of F-actin/focal Talin-Vinculin, and depletion of F-actin-associated postsynaptic proteins. SSH1 reduction, which mitigated Cofilin activation, prevented Abeta42O-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/Abeta-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 beta1-integrin-SSH1-Cofilin pathway in mitochondrial and synaptic dysfunction in AD. |
