Curculigoside, a traditional Chinese medicine monomer, ameliorates oxidative stress in Alzheimer's disease mouse model via suppressing ferroptosis.

Alzheimer's disease (AD) is a neurodegenerative disorder where oxidative stress, induced by ferroptosis, has been linked to neuronal damage and cognitive deficits. The objective of this study is to investigate if the potential therapeutic agent, Curculigoside (CUR), could ameliorate AD by inhibiting ferroptosis. The potential therapeutic targets, such as GPX4 and SLC7A11, were identified using weighted gene co-expression network analysis (WGCNA). Concurrently, CUR was also screened against these potential targets using various analytical methods. For the in vivo studies, intragastric administration of CUR significantly ameliorated cognitive impairment in AD model mice induced by scopolamine and okadaic acid (OA). In vitro, CUR protected neuronal cells by altering the levels of ferroptosis-related specific markers in OA and scopolamine-induced neurotoxicity. The administration of CUR through intragastric route significantly reduced the levels of AD-promoting factors (such as Aß1-42, p-tau) and ferroptosis-promoting factors in the hippocampus and cortex of AD mice. Furthermore, CUR up-regulated the expression of GPX4 and decreased the expression of SLC7A11 in the ferroptosis signaling pathway, thereby increasing the ratio of glutathione (GSH)/oxidized glutathione (GSSG) in vivo and vitro. In conclusion, the cumulative results suggest that the natural compound CUR may serve as a promising therapeutic agent to ameliorate AD by inhibiting ferroptosis.

Sodium butyrate ameliorates the cognitive impairment of Alzheimer's disease by regulating the metabolism of astrocytes.

RATIONALE: Energy metabolism disorder is a widespread feature that exists in the early clinical stages of Alzheimer's disease (AD). Astrocyte is the most numerous and the largest glial cell in the brain. By transporting energetic fuels such as lactate and ketones to neurons, astrocytes play a pivotal role in maintaining the cerebral energy homeostasis. Sodium butyrate (NaB), a type of short-chain fatty acid; its anti-inflammatory effect; and inhibition on histone deacetylases have been widely studied. METHODS: Spatial memory and cognitive ability of mice were assessed by using behavioral tests. Western blotting and ELISA kits were used to detect related protein levels and other biochemical markers, respectively. OBJECTIVES: To prove the therapeutic effect of NaB on AD cognitive impairment and provide possible research ideas for mechanism exploration. RESULTS: Administration of NaB could improve the cognitive impairments induced by Aß25-35 in mice. Furthermore, NaB could promote the differentiation of astrocytes towards A2-neuron-protective subtype, astroglial mitochondrial function, and lactate shuttle between astrocytes and neurons. CONCLUSION: These findings reveal the effect of sodium butyrate on astrocytes, which may improve the pathological status of AD and provide experimental basis for sodium butyrate treatment of AD.

Disrupted ubiquitin proteasome system underlying tau accumulation in Alzheimer's disease.

Accumulation of phosphorylated tau (p-tau) has long been an underappreciated hallmark of Alzheimer's disease. Tau is one of the major components of microtubule networks in neurons, and its abnormal phosphorylation and aggregation are closely related to the impairment of axonal transport. Abnormalities in axonal transport can impede autophagy in neurons, interrupting the autophagic clearance of amyloid beta. The ubiquitin proteasome system (UPS) maintains intracellular proteostasis by degrading abnormal or redundant proteins. Ever-mounting evidence suggests that UPS deficits contribute to p-tau accumulation. And targeting UPS attenuates tau pathology. This review endeavors to exam the potential role of UPS in p-tau aggregation, and how pathogenic tau may inflict other abnormalities such as amyloid beta accumulation in Alzheimer's disease.