Fig. 7
Schematic description of kinase signaling pathways in Alzheimer’s disease. GSK3β, as one of the main kinases involved in tau phosphorylation, adds a phosphate group to the Thr231 site on tau. This process triggers tau oligomerization, NFTs formation, and participates in the regulation of the Nrf2-ARE pathway by phosphorylating Nrf2 Ser334-338 residues, thereby reducing the antioxidant capacity. The CDK5/p35 complex plays a critical role in maintaining synaptic function by modulating STAT3, synaptic components including PSD95 and DARPP32, ErbB3, BDNF/TrkB, or other regulators, while in AD, the CDK5/p35 is cleaved by Ca2+, Aβ, and calpain-1, giving rise to the abnormally hyperactive CDK5/p25 variant, promoting the pathway of cellular apoptosis, reentry into the cell cycle, and mitochondrial dysfunction. The phosphorylation of p38 MAPK exacerbates oxidative stress, decreases synaptic plasticity, and increases the release of inflammatory factors. Meanwhile, overactivated Fyn contributes to the phosphorylation of APP at Tyr682, leading to increased generation of intracellular Aβ. Fyn phosphorylation at Tyr416 causes cellular toxicity and imbalances in neural network function by modulating NMDAR, Pyk2, and eEF2. TTBK1 activates CDK5 and triggers downstream signaling, promoting NMDAR internalization and imbalanced degradation of the neural network. On the other hand, it triggers the phosphorylation of tau protein at Ser422 via calpain-1, exacerbating tau aggregation. In the progression of AD, the reduced activity of AMPK increases the phosphorylation level of mTOR. This, in turn, hinders autophagy processes while concurrently enhancing Aβ generation. The downregulation of PKA expression in AD pathology leads to decreased activation of both SIRT1 and CREB, increasing Aβ production and synaptic plasticity vulnerability. CK1 abnormalities not only regulate the transmission of their inherent signals but also wield regulatory influence over the downstream signaling pathways of crucial kinases such as GSK3β and CDK5. This intricate interplay between kinases forms an interconnected regulatory network that functions in AD. This figure was created with BioRender.com
