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

Abstract

The accumulation of amyloid-β protein (Aβ) 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 Aβ impinges its signals to Cofilin from the neuronal surface are unknown. In this study, we found that Aβ42 oligomers (Aβ42O, amyloid-β protein 1–42 oligomers) bind with high affinity to low or intermediate activation conformers of β1-integrin, resulting in the loss of surface β1-integrin and activation of Cofilin via Slingshot homology-1 (SSH1) activation. Specifically, conditional loss of β1-integrin prevented Aβ42O-induced Cofilin activation, and allosteric modulation or activation of β1-integrin significantly reduced Aβ42O binding to neurons while blocking Aβ42O-induced reactive oxygen species (ROS) production, mitochondrial dysfunction, depletion of F-actin/focal Vinculin, and apoptosis. Cofilin, in turn, was required for Aβ42O-induced loss of cell surface β1-integrin, disruption of F-actin/focal Talin–Vinculin, and depletion of F-actin-associated postsynaptic proteins. SSH1 reduction, which mitigated Cofilin activation, prevented Aβ42O-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/Aβ-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 β1-integrin–SSH1–Cofilin pathway in mitochondrial and synaptic dysfunction in AD.

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

“…Patients presenting with neurological disorders, for example, AD, PD, and Gulf War Illness (GWI), are burdened with a significant number of dysfunctional mitochondria [Federico et al, 2012;Piaceri et al, 2012;Swerdlow, 2012;Chaturvedi and Beal, 2013;Wallace, 2013;Forbes-Hernandez et al, 2014;Nicolson et al, 2014;Pagano et al, 2014;Sodhi et al, 2014;Weisfeld-Adams et al, 2015;Woo et al, 2015]. Mitophagy [Novak, 2012;Ashrafi and Schwarz, 2013;Gomes and Scorrano, 2013;Morris et al, 2014;Pinho et al, 2014;Pinto and Moraes, 2014], a selective subform of autophagy [Choi et al, 2013;Schneider and Cuervo, 2014], is a cellular mechanism for removing dysfunctional mitochondria mediated by PINK1 and PARK2 genes working together Kane and Youle, 2012;Youle and van der Bliek, 2012;Allen et al, 2013;Ashrafi and Schwarz, 2013;Trempe et al, 2013;Redmann et al, 2014;Frake et al, 2015;Pickrell and Youle, 2015].…”

Actin dynamics and cofilin‐actin rods in alzheimer disease

“…). These receptors include the mGluR5 metabotropic receptor and β1‐integrin [Loubet et al, ; Um et al, ; Woo et al, ], neither of which has much in common functionally except for their ability to modulate cofilin activity. Indeed, all of the Aβ receptors with identified signaling pathways have a common theme, activation of pathways that modulate cytoskeletal dynamics at synapses [Geng et al, ; Kim et al, ; Kam et al, ; Henriques et al, ].…”

Peptide regulation of cofilin activity in the CNS: A novel therapeutic approach for treatment of multiple neurological disorders

“…Cofilin phosphoregulation is significantly shifted from the norm in rodent models of many neurological disorders, including AD (Zhao et al, 2006; Woo et al, 2015a; Woo et al, 2015b), autism (Duffney et al, 2015; Liu et al, 2016), manic/bipolar disorder (Lee et al, 2016), sleep deprivation (Havekes et al, 2016), neonatal isolation (Tada et al, 2016), and neuropathic pain (Qiu et al, 2016) (Table 1). Dendritic spine shrinkage occurs as a result of cofilin hyperactivation (dephosphorylation) and has been observed in hippocampal neurons during establishment of long-term depression (Figure 2; Zhou et al, 2004), and in neurons of the hippocampus but not the prefrontal cortex of sleep deprived mice (Havekes et al, 2016).…”

“…Indeed, PrP C was found to be necessary for cognitive deficits in a mouse AD model (Table 1; Gimbel et al, 2010). PrP C is a required co-receptor for binding of Aβ to β1-integrin (Woo et al, 2015a) and mGluR5 (Haas et al, 2016). Furthermore, Aβ-binding to β1-integrin signals in a PrP C -dependent manner through RanBP9, a scaffolding protein and nuclear import factor, leading to cofilin dephosphorylation by SSH (Woo et al, 2015b).…”

“…Furthermore, Aβ-binding to β1-integrin signals in a PrP C -dependent manner through RanBP9, a scaffolding protein and nuclear import factor, leading to cofilin dephosphorylation by SSH (Woo et al, 2015b). In a mouse model of AD (Table 1), decreasing RanBP9 or cofilin expression by crosses with RanBP9 or cofilin hemizygous mice results in protection from learning and memory defects in a contextual fear conditioning response, indicating the importance of cofilin activity levels in hippocampal learning and memory (Woo et al, 2015a; Woo et al, 2015b). …”