Glycogen synthase kinase-3 beta, Amyloid-beta precursor protein, Cyclin-dependent kinase 5, and Beta-secretase 1 (GSK3B, APP, CDK5, BACE1)

This target set represents the primary pathological axis of Alzheimer's disease, encompassing both the amyloid-beta (Aβ) and tau protein pathways. Amyloid-beta precursor protein (APP) is a transmembrane protein that, when cleaved by the rate-limiting enzyme Beta-secretase 1 (BACE1), produces Aβ peptides which aggregate into neurotoxic plaques. Simultaneously, Glycogen synthase kinase-3 beta (GSK3B) and Cyclin-dependent kinase 5 (CDK5) are the principal kinases responsible for the hyperphosphorylation of tau protein, leading to the formation of neurofibrillary tangles and microtubule destabilization. There is significant crosstalk between these pathways, as GSK3B has been shown to regulate BACE1 expression and APP processing, while CDK5 activity further modulates tau pathology and neuronal survival. Therapeutic strategies targeting this group include BACE1 inhibitors to reduce Aβ production, monoclonal antibodies to clear APP-derived plaques, and kinase inhibitors to prevent tau-mediated toxicity. Despite extensive clinical efforts, targeting these molecules has faced significant challenges, including safety concerns like ARIA and the need for early intervention before irreversible damage occurs.

Other names

GSK3betaAmyloid precursor proteinABPPAPPIPSS1Beta-secretase 1Asp2Memapsin-2

Inhibition of beta-secretase activity to reduce amyloid-beta production; inhibition of tau phosphorylation via kinase modulation; clearance of amyloid-beta aggregates using monoclonal antibodies; and regulation of APP processing pathways.