Investigating exocyst inhibition for reducing neuronal pathophysiologies associated with Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia among older adults. It is characterized by memory loss, cognitive decline, and hallmark features such as amyloid beta (Aβ) plaques, tau tangles, and metabolic dysfunction. While Aβ accumulation results from amyloidogenic cleavage of the amyloid precursor protein (APP), the upstream trafficking mechanisms that regulate this process remain unclear. The exocyst complex, an evolutionarily conserved eight-protein vesicle tethering complex, has been proposed to guide APP trafficking and support neuronal homeostasis. This study investigates the role of the exocyst in modulating APP processing and AD-related phenotypes in differentiated SH-SY5Y neurons expressing familial APP mutations (Swedish and Indiana). Using genetic knockdown of Exoc5 and pharmacological inhibition with Endosidin2 (ES2), we examined effects on endosomal morphology, Aβ production, tau phosphorylation, metabolic function, and gene expression. Our findings demonstrate that exocyst disruption did not rescue APP-induced dysfunction but instead exacerbated endosomal defects, mitochondrial impairment, and expression of genes associated with apoptosis and inflammation. These results suggest that the exocyst complex is essential for neuronal integrity and that its inhibition may worsen rather than alleviate AD-related cellular pathologies.