Mechanosensitive apoptosis in Alzheimer’s disease

The incidence of neurodegenerative diseases is increasing exponentially, with Alzheimer’s disease (AD) being a notorious example. AD is a progressive, aging-related, multifactorial disease, and no uniform theory exists regarding its etiology. One hypothesis implicates defects in the organism’s mechanosensing and mechanotransduction mechanisms. The deleterious effects of mechanical stress in neurodegeneration have been proven through multiple studies and observations, but the pathways linking mechanical inputs to disease progression remain unclear. It has been proposed that the nervous tissue primarily responds to mechanical stress sources through astrocytes and microglia, with the activation of Piezo1 and TRPV4 ion channels. An area of current research is examining the theory that mechanotransduction might be involved in elevated oxidative stress and dysregulated apoptotic pathways. We have summarized the current understanding of the apoptotic pathways related to AD. Our review has indicated that the relationship between the crucial mechanosensing Hippo pathway (MST1 in humans) and TRPV4 and KCNN4 is worth following up in future studies. We noted that G3BP1 and G3BP2 in FlnA-mediated mechanosensing are linked to ceramide production, along with their interaction with the stress granules - a key element for the onset of apoptosis, which are assembled, among others, in response to oxidative stress. This review sheds light on how the response to mechanical input disrupts apoptotic pathways and what the implications in AD progression and also identifies potential targets for future research focus.