Alzheimer’s Disease: A Review of Molecular Mechanisms and Therapeutic Implications by Targeting Sirtuins, Caspases, and GSK-3

Alzheimer’s disease (AD) is a neurodegenerative disease with a significant impact on global public health. The primary hallmarks of the disease included amyloid-beta peptide (Aβ) deposition, neurofibrillary tangles (NFT), and synaptic loss. Sirtuins, a group of NAD⁺-dependent deacetylase enzymes, are key regulators of AD pathogenesis. SIRT1, a member of sirtuins, has been identified to possess neuroprotective properties. Thus, its promising enhancers are included. Further, SIRT2 promising inhibitors are reviewed for therapeutic efficacy. The extrinsic and intrinsic apoptotic pathways of caspases are mediated by CD95 and DNA damage. The promising inhibitors Q-VD-OPh and minocycline are found to be specific for caspase-7 and caspase-3, respectively. Primarily, glycogen synthase kinase-3β (GSK-3β) is found to be involved in the generation of phosphorylated tau. The promising GSK-3 inhibitor included the COB-187 (IC₅₀ = 370 nM) and maleimide-derivative (compound 33, IC₅₀ = 0.09 μM). This review highlights the molecular mechanisms of sirtuin, caspase, and GSK-3 in the pathophysiology of AD. Further, promising modulators specific to these targets are described.