Phytochemicals targeting Alzheimer's disease via the AMP-activated protein kinase pathway, effects, and mechanisms of action

Alzheimer's disease (AD), characterized by cognitive dysfunction and other behavioral abnormalities, is a progressive neurodegenerative disease that occurs due to aging. Currently, effective drugs to mitigate or treat AD remain unavailable. AD is associated with several abnormalities in neuronal energy metabolism, such as decreased glucose uptake, mitochondrial dysfunction, and defects in cholesterol metabolism. Amp-activated protein kinase (AMPK) is an important serine/threonine protein kinase that regulates the energy status of cells. AMPK is widely present in eukaryotic cells and can sense and regulate energy metabolism to maintain energy supply and demand balance, making it a promising target for energy metabolism-based AD therapy. Therefore, this review aimed to discuss the molecular mechanism of AMPK in the pathogenesis of AD to provide a theoretical basis for the development of new anti-AD drugs. To review the mechanisms of phytochemicals in the treatment of AD via AMPK pathway regulation, we searched PubMed, Google Scholar, Web of Science, and Embase databases using specific keywords related to AD and phytochemicals in September 2023. Phytochemicals can activate AMPK or regulate the AMPK pathway to exert therapeutic effects in AD. The anti-AD mechanisms of these phytochemicals include inhibiting Aβ aggregation, preventing Tau hyperphosphorylation, inhibiting inflammatory response and glial activation, promoting autophagy, and suppressing anti-oxidative stress. Additionally, several AMPK-related pathways are involved in the anti-AD mechanism, including the AMPK/CaMKKβ/mTOR, AMPK/SIRT1/PGC-1α, AMPK/NF-κB/NLRP3, AMPK/mTOR, and PERK/eIF2α pathways. Notably, urolithin A, artemisinin, justicidin A, berberine, stigmasterol, arctigenin, and rutaecarpine are promising AMPK agonists with anti-AD effects. Several phytochemicals are effective AMPK agonists and may have potential applications in AD treatment. Overall, phytochemical-based drugs may overcome the barriers to the effective treatment of neurodegenerative diseases.