Regulation of different kinases for Alzheimer's disease therapy: progresses and perspectives

Alzheimer's disease (AD) is clinically characterized by extracellular amyloid plaques caused by β-amyloid (Aβ) aggregation and intracellular neurofibrillary tangles (NFTs) formed by hyperphosphorylation of tau protein. Plaques and tangles attract microglia to their periphery, causing them to adopt the proinflammatory M1 type. In the central nervous system (CNS), activated microglia are a major source of inflammatory molecules, which trigger a positive feedback mechanism that activates more microglia, which further aggravates the neuroinflammatory response. In this procedure, many kinases are involved in the main signaling pathways of microglia activation. Kinases phosphorylate different substrate proteins, thereby regulating various processes of AD occurrence and development. Therefore, many researchers have developed kinase modulators to reduce the phosphorylation process of downstream substrates, in order to achieve the effect of AD treatment.