Differential senolytic inhibition of normal versus Aβ-associated cholinesterases: implications in aging and Alzheimer's disease

Cellular senescence is a hallmark of aging and the age-related condition, Alzheimer's disease (AD). How senescence contributes to cholinergic and neuropathologic changes in AD remains uncertain. Furthermore, little is known about the relationship between senescence and cholinesterases (ChEs). Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are important in neurotransmission, cell cycle regulation, and AD amyloid-β (Aβ) pathology. Senolytic agents have shown therapeutic promise in AD models. Therefore, we evaluated in vitro and in silico activity of senolytics, dasatinib (1), nintedanib (2), fisetin (3), quercetin (4), GW2580 (5), and nootropic, meclofenoxate hydrochloride (6), toward AChE and BChE. As ChEs associated with AD pathology have altered biochemical properties, we also evaluated agents 1-6 in AD brain tissues. Enzyme kinetics showed agents 1, 3, 4, and 6 inhibited both ChEs, while 2 and 5 inhibited only AChE. Histochemistry showed inhibition of Aβ plaque-associated ChEs (1 and 2: both ChEs; 5: BChE; 6: AChE), but not normal neural-associated ChEs. Modeling studies showed 1-6 interacted with the same five binding locations of both ChEs, some of which may be allosteric sites. These agents may exert their beneficial effects, in part, by inhibiting ChEs associated with AD pathology and provide new avenues for development of next-generation inhibitors targeting pathology-associated ChEs.