Alzheimer’s disease (AD) is a devastating brain disorder that slowly erodes memory, thinking, and independence. Two hallmark features of AD are the buildup of amyloid beta plaques outside neurons and tau tangles inside them. Current therapies targeting amyloid beta provide only modest benefits and do not halt disease progression, partly because we still do not fully understand how amyloid beta outside neurons triggers the damaging tau changes within them. Our research focuses on a process that may connect these two pathologies: amyloid beta-induced damage to neuronal membranes. When membranes are injured, calcium balance inside neurons is disrupted, leading to the formation of abnormal, swollen nerve cell processes called dystrophic neurites. These neurites may act as hotspots where tau pathology begins and spreads. We are studying Annexin A6 (A6), a naturally occurring protein that helps repair damaged membranes. We will first test whether loss of A6 worsens membrane injury, calcium imbalance, and tau pathology in neurons and mouse models of AD. Next, we will evaluate whether supplying recombinant A6 protein directly to the brain can restore membrane integrity, reduce neurite damage, rebalance calcium, and prevent tau accumulation. This work aims to clarify how membrane damage links Aβ to tau and to test A6 as a potential therapy. By showing that enhancing membrane repair can protect neurons at their point of injury, we hope to open the door to treatments that not only slow symptoms but also prevent disease progression, preserving brain health and independence.
