Slingshot-Cofilin activation mediates mitochondrial and synaptic dysfunction via Aβ ligation to β1-integrin conformers

• Published in: Cell death and differentiation Vol. 22; no. 6; pp. 921 - 934
• Main Authors: Woo, J A, Zhao, X, Khan, H, Penn, C, Wang, X, Joly-Amado, A, Weeber, E, Morgan, D, Kang, D E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-06-2015; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/109; 13/89; 14-3-3 protein; 14/19; 14/34; 64/110; 692/699/375; 82/80; 9/30; 96/95; Actin; Actin Depolymerizing Factors - genetics; Actin Depolymerizing Factors - metabolism; Allosteric properties; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid precursor protein; Animals; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cell Line; Cell surface; CHO Cells; Cofilin; Cricetulus; Electrophysiology; Gliosis; Hippocampus - metabolism; Homology; Humans; Immunoblotting; Integrin beta1 - genetics; Integrin beta1 - metabolism; Life Sciences; Long-term potentiation; Mice; Mitochondria; Mitochondria - metabolism; Neurodegenerative diseases; Oligomers; Original Paper; Phosphoprotein Phosphatases - genetics; Phosphoprotein Phosphatases - metabolism; Presenilin 1; Protein Binding; Proteins; Reactive oxygen species; Reactive Oxygen Species - metabolism; Stem Cells; Synapses - metabolism; Talin; Vinculin; β-Amyloid
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2015.5

The accumulation of amyloid-
β
protein (A
β
) 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
β
impinges its signals to Cofilin from the neuronal surface are unknown. In this study, we found that A
β
42 oligomers (A
β
42
O
, amyloid-
β
protein 1–42 oligomers) bind with high affinity to low or intermediate activation conformers of
β
1-integrin, resulting in the loss of surface
β
1-integrin and activation of Cofilin via Slingshot homology-1 (SSH1) activation. Specifically, conditional loss of
β1-integrin
prevented A
β
42
O
-induced Cofilin activation, and allosteric modulation or activation of
β
1-integrin significantly reduced A
β
42
O
binding to neurons while blocking A
β
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
β
42
O
-induced loss of cell surface
β
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
β
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
β
-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
β
1-integrin–SSH1–Cofilin pathway in mitochondrial and synaptic dysfunction in AD.