Membrane-Cytoskeleton Connectivity in Alzheimer’s Disease:From Aβ Clearance to TauSpreading by Microglia

Alzheimer’s disease (AD) is a progressive irreversible neurodegenerative disease affecting about 5.8 million Americans. There’s no cure for AD yet. Amyloid plaques and neurofibrillary tangles are two hallmarks of AD. And their major component, Amyloid-beta (Aβ) and tau protein may be responsible for the cause and progression of AD. Microglia is a type of glial cell important for maintaining brain homeostasis. Cytosolic phospholipase A2 (cPLA2) cleaves phospholipid, the main component of cellular membrane, and release signaling molecules. In this study, we explored the impact of cPLA2 on membrane physical properties such as membrane cytoskeleton connectivity and related signaling pathways in microglia. Effects of cPLA2 on oligomeric Aβ clearance and Tau propagation in AD were also investigated. Our study showed that inhibition of cPLA2 activity increased the membrane cytoskeleton connectivity leading to attenuated oligomeric Aβ uptake by microglia. The results also suggested that inhibition of cPLA2 with arachidonyl trifluoromethyl ketone increased the production of exosomes secreted by microglia fed with Tau. Detailed mechanism on how ATK and cPLA2 affect the production of exosome in microglia and spreading of Tau through exosome will be explored with future experiments. Together, this study provided insight for Aβ clearance and Tau spreading in AD by altering cPLA2 activity in microglia and may be helpful for the development of AD treatments.