Shen_2026_Neurosci_601_155

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by beta-amyloid (Abeta) deposition, tau hyperphosphorylation, neuroinflammation, and cholinergic dysfunction. Currently, no disease-modifying drugs are available, and existing symptomatic treatments offer limited efficacy while posing safety concerns, highlighting the urgent need for multitarget therapeutic strategies. The natural betacarboline alkaloid harmine has attracted considerable attention due to its favorable blood-brain barrier penetration and multitarget profile. Accumulating preclinical evidence indicates that harmine can concurrently modulate several core pathological processes of AD. Mechanistically, it potently inhibits dualspecificity tyrosine phosphorylationregulated kinase 1A (DYRK1A), thereby reducing tau hyperphosphorylation, suppressing aberrant amyloid precursor protein processing, and enhancing neprilysinmediated Abeta clearance. Concurrently, harmine attenuates neuroinflammation via negative regulation of the Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NFkappaB) and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathways, improves cholinergic neurotransmission through acetylcholinesterase inhibition, and alleviates glutamate excitotoxicity by upregulating astrocytic glutamate transporter 1/excitatory amino acid transporter 2 (GLT-1/EAAT2) expression. Structurally optimized harmine derivatives have demonstrated enhanced dual inhibitory activity and improved cognitive outcomes in preclinical models. Despite these promising findings, challenges such as pharmacokinetic limitations, insufficient target selectivity, and a lack of clinical data remain. In conclusion, the harmine scaffold represents a mechanistically grounded and promising direction for the development of multitarget therapeutics for AD.