Ferjancic Benetik_2024_Pharmacol.Ther__108748

The simultaneous targeting of neuroinflammation and cholinergic hypofunction, the key pathological changes in Alzheimer's disease (AD), is not addressed by drugs currently in clinical trials, highlighting a critical therapeutic gap. We propose that dual-acting small molecules that inhibit butyrylcholinesterase (BChE) and mitogen-activated protein kinase p38alpha (p38alpha MAPK) represent a novel strategy to combat AD. This hypothesis is supported by cellular and animal studies as well as in silico modeling showing that it is possible to act simultaneously on both enzymes. Amyloid beta (Abeta) plaques trigger a pro-inflammatory microglial response that overactivates p38alpha MAPK, leading to increased Abeta synthesis, tau hyperphosphorylation, and altered synaptic plasticity. Overactivated microglia exacerbate neuroinflammation and cholinergic degeneration, ultimately leading to cognitive impairment. Structural similarities between the binding sites of BChE and p38alpha MAPK provide a promising basis for the development of dual inhibitors that could alleviate AD symptoms and address the underlying pathology.