Dual inhibition of butyrylcholinesterase and p38α mitogen-activated protein kinase : a new approach for the treatment of Alzheimer's disease

Ferjančič Benetik, Svit (author), Knez, Damijan (author), Obreza, Aleš (author), Košak, Urban (author), Gobec, Stanislav (author)

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.

• Language: English
• Keywords: Alzheimer's disease, neuroinflammation, butyrylcholinesterase, p38α mitogen-activated protein kinase, neurodegeneration, selectivity
• Work type: Article
• Typology: 1.02 - Review Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: 13 str.
• Numbering: Vol. 264, art. 108748
• PID: 20.500.12556/RUL-164882
• UDC: 616.894
• ISSN on article: 0163-7258
• DOI: 10.1016/j.pharmthera.2024.108748
• COBISS.SI-ID: 215038723
• Publication date in RUL: 15.11.2024

Record is a part of a journal

• Title: Pharmacology & therapeutics
• Shortened title: Pharmacol. ther.
• Publisher: Elsevier
• ISSN: 0163-7258
• COBISS.SI-ID: 26118144

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: Alzheimerjeva bolezen, nevrovnetje, butirilholinesteraza, p38α mitogen aktivirana protein kinaza, nevrodegeneracija, nevrodegenerativne bolezni