Pathophysiological signaling and therapeutic potential of protein kinases in Alzheimer’s disease: A comprehensive review

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is characterized by the formation of plaques of amyloid proteins and tangles of tau proteins, which disrupt neuronal communication and eventually lead to neuronal death. The pathological mechanisms underlying AD are complex, with tau protein hyperphosphorylation playing a central role in disease progression. Several kinases, including microtubule affinity-regulating kinase (MARK), cyclin-dependent kinase-5 (CDK-5), and glycogen synthase kinase-3 (GSK-3), have been identified as key regulators of tau phosphorylation. Abnormal activity of these enzymes has been associated with hyperphosphorylation of tau proteins, leading to synaptic dysfunction, neuronal death, and impaired memory. Moreover, other protein kinases, such as protein kinase C and Rho kinase, contribute to neurodegeneration by disrupting intracellular signaling essential for neuronal survival. Given these critical roles of such enzymes in AD pathogenesis, several therapeutic strategies targeting tau-associated pathways have gained significant attention in recent years. Multiple clinical trials are also underway to develop effective anti-tau treatments, including drugs targeting tyrosine kinases, GSK-3, and mitogen-activated protein kinase (MAPK). Over the past decades, there has been a growing research emphasis on the role of protein kinases in AD and on identifying and validating potential enzymatic targets for AD management. This review provides an in-depth analysis of the molecular mechanisms by which various protein kinases induce tau-associated neurodegeneration and emphasizes emerging therapeutic strategies targeting kinase-mediated signaling pathways, offering new perspectives for AD management.