Natural glycosides as multi-target neuroprotective agents in Alzheimer’s disease: Bridging mechanistic insights and translational potential

• Natural glycosides target Aβ aggregation, tau phosphorylation, and cholinergic dysfunction in AD. • 2. Glycosides mitigate mitochondrial dysfunction and oxidative stress to counteract neurodegeneration. • Glycosides restore gut microbiota and gut-brain axis, linking peripheral dysbiosis to cognitive decline. • Glycosides improve autophagy-lysosome dysfunction, extending beyond mitochondria-focused therapy. • Nanotechnology enables brain-targeted glycoside delivery, enhancing clinical potential. Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder defined by pathologies including amyloid-beta (Aβ) aggregation, tau hyperphosphorylation, and neuroinflammation. Natural glycosides, safe compounds derived from plants, have emerged as promising multi-target neuroprotective agents for treating this complex disease. This review synthesizes the mechanistic evidence for natural glycosides in AD, examining their effects on key pathological pathways like Aβ production, tau phosphorylation, cholinergic neurotransmission, and neuroinflammation. It also addresses significant translational challenges, including poor bioavailability and blood-brain barrier (BBB) penetration, and outlines potential delivery strategies. Evidence indicates that natural glycosides exert multi-target effects, modulating Aβ and tau pathology while restoring cholinergic function. They also mitigate mitochondrial dysfunction, oxidative stress, and inhibit ferroptosis. Despite these benefits, their therapeutic application is currently hindered by poor oral bioavailability and limited penetration of the BBB. Natural glycosides are credible multi-target candidates for AD therapy. Overcoming their pharmacokinetic limitations through brain-targeted delivery strategies, such as nanotechnology and intranasal approaches, is critical for their clinical success. Future research must prioritize advancing these compounds from preclinical studies to rigorous clinical trials to meet the urgent therapeutic need in AD.