Polygonatum Sibiricum polysaccharide ameliorates Alzheimer's disease by alleviating cuproptosis and activating the PI3K/AKT signaling pathway.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Defined by the selective loss of central nervous system neurons, a progressive neurodegenerative disorder is what Alzheimer's disease (AD) constitutes. It is recognized as the leading cause of dementia globally. Polygonatum sibiricum, also known as "tiger ginger" and "chicken-head ginseng", was hailed as a "treasure herb" by the ancient Chinese pharmacologist Li Shizhen. As a traditional Chinese medicine, its primary active component, Polygonatum sibiricum polysaccharide (PSP), has demonstrated well-defined neuroprotective effects. AIM OF THE STUDY: The core objective of the present research was to dissect the molecular mechanisms that underlie the therapeutic actions of PSP in AD. MATERIALS AND METHODS: PSP was purified through water extraction, alcohol precipitation, decolorization, Sevag method deproteinization, and dialysis. The purified polysaccharide was characterized by ultraviolet and infrared spectroscopy. Spatial learning was evaluated as examined by performance in the Morris water maze. To investigate the pathological processes involved in PSP's effects, a range of techniques were employed, including Nissl staining, biochemical assays, immunohistochemistry, transmission electron microscopy, immunofluorescence, and western blotting. The interaction between PSP and the DLAT protein was examined using the CETSA. RESULTS: Experimental findings indicated that administration of PSP mitigated cognitive impairments in mice with AD and attenuated the loss of neuronal cells. Furthermore, PSP ameliorated mitochondrial damage, modulated cuproptosis-related proteins, and activated the phosphorylation of PI3K and AKT. CONCLUSION: The present study demonstrates that PSP improves cognitive impairments in 3 × Tg-AD mice by targeting DLAT and subsequently activating the PI3K/AKT pathway. The findings from in vitro cellular models align with those observed in vivo studies. Consequently, PSP emerges as a promising agent endowed with therapeutic potential for AD treatment.