Abstract
Amyloid β (Aβ) accumulation is an early event in the pathogenesis of Alzheimer’s disease (AD), leading to mitochondrial and synaptic dysfunction, tau accumulation, and eventual neuronal death. While the p53 apoptotic pathway has clearly been associated with Aβ deposits and neuronal apoptosis, the critical upstream factors contributing to p53 activation in AD are not well understood. We have previously shown that cofilin activation plays a pivotal role in Aβ-induced mitochondrial and synaptic dysfunction. In this study, we show that activated cofilin (S3A) preferentially forms a complex with p53 and promotes its mitochondrial and nuclear localization, resulting in transcription of p53-responsive genes and promotion of apoptosis. Conversely, reduction of endogenous cofilin by knockdown or genetic deficiency inhibits mitochondrial and nuclear translocation of p53 in cultured cells and in APP/PS1 mice. This cofilin-p53 pro-apoptotic pathway is subject to negative regulation by PLD1 thorough cofilin inactivation and inhibition of cofilin/p53 complex formation. Finally, activated cofilin is unable to induce apoptosis in cells genetically lacking p53. These findings taken together indicate that cofilin coopts and requires the nuclear and mitochondrial pro-apoptotic p53 program to induce and execute apoptosis, while PLD1 functions in a regulatory multi-brake capacity in this pathway.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative condition in which amyloid β (Aβ) peptide accumulation and hyperphosphorylated tau aggregation are the major pathological hallmarks
Multiple studies have shown that Phospholipase D 1 (PLD1) exerts a protective role in programmed cell death (PCD)[27], and that its activity is induced by carbachol[25]
Multiple studies have shown that activated cofilin can induce toxicity and cell death directly as a result of its translocation to mitochondria, leading to opening of the mitochondrial permeability transition pore, reducing Δψm, releasing cytochrome c, and activating caspases[37, 50]
Summary
Alzheimer’s disease (AD) is a neurodegenerative condition in which amyloid β (Aβ) peptide accumulation and hyperphosphorylated tau aggregation are the major pathological hallmarks. Our previous study showed that Aβ-induced mitochondrial dysfunction is mediated by Slingshot-1 homolog (SSH1)-dependent activation of cofilin, which leads to the translocation of cofilin to mitochondria[1, 2]. While current studies indicate that the active dephosphorylated cofilin exerts pro-apoptotic activity via its ability to translocate to mitochondria[9, 10], other mechanisms that regulate or mediate cofilin-induced neurotoxicity are completely unknown. The process of p53 trafficking is associated with cytoskeletal proteins including actin and microtubules. We report on a novel tripartite molecular link between cofilin and p53-mediated apoptotic pathways and show the upstream and downstream interdependence of cofilin and p53 for the induction and execution of mitochondrial dysfunction and apoptosis, while PLD1 functions as a regulatory multi-brake system in this pathway
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