20.500.12556/RUL-164882 Dual inhibition of butyrylcholinesterase and p38α mitogen-activated protein kinase a new approach for the treatment of Alzheimer's disease 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 p38α (p38α MAPK) represent a novel strategy to combat AD. This hypothesis is supported by cellular and animal studies as well as in silico modelling showing that it is possible to act simultaneously on both enzymes. Amyloid beta (Aβ) plaques trigger a pro-inflammatory microglial response that overactivates p38α MAPK, leading to increased Aβ 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 p38α MAPK provide a promising basis for the development of dual inhibitors that could alleviate AD symptoms and address the underlying pathology. Alzheimer's disease neuroinflammation butyrylcholinesterase p38α mitogen-activated protein kinase neurodegeneration selectivity Alzheimerjeva bolezen nevrovnetje butirilholinesteraza p38α mitogen aktivirana protein kinaza nevrodegeneracija nevrodegenerativne bolezni true false true Angleški jezik Slovenski jezik Članek v reviji 2024-11-15 08:31:24 2024-11-15 08:31:31 2024-11-22 14:56:30 0000-00-00 00:00:00 2024 0 0 13 str. Vol. 264, art. 108748 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616.894 0163-7258 10.1016/j.pharmthera.2024.108748 215038723 1-s2.0-S0163725824001682-main.pdf 1-s2.0-S0163725824001682-main.pdf 1 D8D3AC04077BC139EE946151BA944B61 45a30de0145f0579a0f0d91abd142610d3e5ee384150da258628f02ab0c3538a 80199992-a323-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=195703 https://www.sciencedirect.com/science/article/pii/S0163725824001682 1 4444b55f-a323-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=195702 Fakulteta za farmacijo 0 0 0