oAβ and oTau-Induced Endothelial Dysfunction in Alzheimer's: Impact on BBB Integrity & Insulin Signaling

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that has become a serious health and social concern with the increasing aging population. Currently, approximately 47 million people worldwide suffer from AD, and this number is expected to rise to around 131 million by 2050. Growing evidence indicates that vascular dysfunction is a key contributor to the pathogenesis of AD. Cerebral endothelial cells (CECs), one of the major cell types in the brain, play a vital role in angiogenesis, blood vessel formation, and maintaining blood-brain barrier (BBB) integrity. They also mediate insulin signaling within the brain, which is essential for proper brain function. Dysfunction of CECs has been implicated in the pathology of various neurovascular disorders, including AD. Although pathological protein aggregates associated with AD, such as oligomeric amyloid-β (oAβ) and oligomeric tau (oTau), have been shown to impair neuronal and cognitive function, their direct interactions with CECs and the resulting functional effects remain incompletely understood. In this Ph.D. thesis, I demonstrate that oAβ and oTau induce biochemical and biomechanical alterations in CECs, including changes in rolling adhesion mechanics, oxidative stress, inflammatory responses, cytoskeleton reorganization, tight junction protein expression, BBB integrity, and insulin signaling. These alterations are mediated through the RhoA/ROCK and cPLA2 pathways. Collectively, this study advances our understanding of the interplay between neurodegeneration, endothelial dysfunction, and metabolic dysregulation in AD, offering new avenues for therapeutic intervention.