Aug 2026· Journal of Dietary Supplements· pp.
1-20
· 0 citations· 29 references
Medicine
TL;DR
Nacre supplementation was associated with improved performance in the Y-maze and novel object recognition tests, reduced amyloid-β deposition and Congo red-positive plaque burden, lower phosphorylated tau immunoreactivity, and fewer histologically degenerated hippocampal neurons.
Abstract
Alzheimer's disease is characterized by cognitive decline, amyloid-β deposition, tau-related pathology, neuroinflammation, and oxidative stress. Pearl oyster shell-derived nacre extract is used in dietary supplement-related applications, but evidence from animal models should be interpreted cautiously and its effects on Alzheimer's disease-like pathology remain incompletely defined. To evaluate whether long-term oral dietary supplementation with nacre extract is associated with changes in cognitive performance and Alzheimer's disease-like pathological features in APPNL-G-F/NL-G-F knock-in mice. A controlled preclinical animal study was performed using male C57BL/6 wild-type mice and male APPNL-G-F/NL-G-F knock-in mice over a 6-month dietary supplementation period. Six mice were assigned to each group. APP knock-in mice received a standard diet with or without 0.5% (w/w) nacre extract, corresponding to an estimated intake of approximately 20 mg/mouse/day or approximately 600 mg/kg/day. Cognitive performance was assessed using the Y-maze and novel object recognition tests. Brain pathology and molecular responses were evaluated by histology, immunohistochemistry, RNA sequencing, qPCR, Western blotting, and oxidative stress-related assays. Nacre supplementation was associated with improved performance in the Y-maze and novel object recognition tests, reduced amyloid-β deposition and Congo red-positive plaque burden, lower phosphorylated tau immunoreactivity, and fewer histologically degenerated hippocampal neurons. Exploratory RNA sequencing of non-microdissected brain tissue excluding the cerebellum (n = 3/group) identified 53 genes meeting the criteria of an absolute fold change ≥ 1.5 and a valid non-zero FDR-adjusted p value < 0.05. A2M showed a 1.51-fold increase (FDR-adjusted p = 0.00091), and increased A2M abundance was confirmed at the protein level. Iba1 and GFAP immunoreactivity was reduced, and oxidative stress-related parameters were altered in the nacre-supplemented group. Long-term nacre supplementation was associated with improvements in behavioral performance and attenuation of several Alzheimer's disease-like pathological features in male APP knock-in mice. These findings represent an exploratory preclinical signal and do not establish a causal mechanism, dose-response relationship, comprehensive safety profile, or efficacy as a dietary supplement in humans.
OBJECTIVE
Given the global aging intensification, age-related chronic diseases like Alzheimer's disease (AD) severely harm the elderly's health, with unclear pathogenesis and no effective drugs. Thus, this study intervened in APP/PS1 mice with docosahexaenoic acid (DHA) feeds of different doses to explore DHA's effects on the mice's cognitive function and nerve cell apoptosis, aiming to find the ways to prevent or delay the elderly's cognitive decline.
METHODS
Six-month-old APP/PS1 mice were divided into 4 groups: wild control (WT), model control (Con), low-dose DHA (DHA-L), and high-dose DHA (DHA-H). After intervention, the study evaluated mice's cognitive function, determined brain AD-related protein and free fatty acid levels, assessed neuronal degeneration and apoptosis, measured telomere oxidative damage, telomere length, and brain oxidative stress levels.
RESULTS
(1) DHA shortened water maze escape latency, increased platform crossings and target quadrant residence time, and reduced the expression of AD-related proteins (APP, Aβ, etc.) (P < 0.05); (2) It improved brain neuronal degeneration and apoptosis (P < 0.05); (3) It enhanced brain antioxidant capacity, regulated SOD, LPO, and MDA levels, and reduced DNA and telomere oxidative damage (P < 0.05); (4) It prolonged brain telomere length (P < 0.05).
CONCLUSION
DHA supplementation can improve cognitive decline in AD model mice, and the mechanism may be that DHA supplementation alleviates oxidative stress-mediated telomere wear in brain tissue, thereby inhibiting apoptosis of neuronal cells. These conditions provide a scientific basis for the elderly and people with cognitive impairment to prevent or alleviate cognitive impairment with reasonable intake of DHA.
Emerging evidence indicates that the neuroprotective effects of
Astragalus polysaccharides
(APS), an extract compound and bioactive constituent derived from traditional Chinese herbs, may be relevant to an effective prescription for delaying progression of Alzheimer’s disease (AD), yet the underlying mechanisms remain to be fully elucidated. This study aimed to investigate the therapeutic efficacy of APS in alleviating cognitive impairment and neuropathology in 5×FAD transgenic mice, with a specific focus on the regulatory role of the gut-brain axis.
Male 5×FAD mice were orally administered APS (200 mg/kg/day) for 60 days. General observations were conducted to assess the
in vivo
tolerance of APS. Cognitive function was evaluated using the Morris water maze (MWM). Neuropathological assessments included immunofluorescence and Western blotting for amyloid-β (Aβ) deposition, synaptic proteins, and neuroinflammatory markers. Gut microbiota composition and metabolic profiles were analyzed via 16S rRNA gene sequencing and targeted metabolomics. Furthermore, fecal microbiota transplantation (FMT) was performed to verify the causal contribution of gut microbiota to the observed therapeutic effects.
APS administration was well-tolerated throughout the study period, with no overt toxic effects observed. Moreover, APS administration significantly ameliorated spatial learning and memory deficits in 5×FAD mice. Mechanistically, APS treatment reduced Aβ plaque burden, restored synaptic protein expression (PSD-95 and Syntaxin), and attenuated microglia-mediated neuroinflammation by suppressing pro-inflammatory cytokines (IL-6, TNF-α) and upregulating TREM2. Microbiome analysis revealed that APS reshaped gut microbial diversity and composition, enriching beneficial taxa such as
Lactobacillus
. Metabolomics indicated a partial restoration of amino acid metabolism. Notably, FMT from APS-treated donors successfully reproduced the cognitive improvements and anti-inflammatory effects in recipient mice.
These findings demonstrate that APS alleviates cognitive deficits and AD-like pathology, partially through remodeling gut microbiota and modulating the gut-brain axis. APS represents a promising natural compound-based therapeutic candidate for managing cognitive decline associated with Alzheimer’s disease.
Xiaolin Cui, Zhen Wei, Qingshui Wang et al.· Frontiers in Pharmacology· 0 citations
Age-related cognitive impairment is a major public health concern associated with neuroinflammation and gut microbiota dysbiosis. Proanthocyanidins (PC), a class of dietary polyphenols, have been suggested to modulate the gut-brain axis. Here, we investigated the mechanisms by which PC alleviate cognitive deficits in a thyroxine-induced accelerated aging-like mouse model. PC supplementation significantly improved spatial learning and memory, as assessed by the Morris water maze. These effects were accompanied by modulation of gut microbiota composition and altered fecal short-chain fatty acids (SCFAs), particularly butyrate and propionate. PC also improved intestinal barrier function, increased colonic tryptophan hydroxylase 1 (TPH1) expression, and regulated 5-hydroxytryptophan (5-HTP)/serotonin (5-HT)-related pathways. In parallel, hippocampal neuroinflammatory responses were attenuated. Collectively, these findings suggest that the neuroprotective effects of PC are associated with a gut microbiota-SCFAs-5-HTP/5-HT axis. This study highlights the potential of dietary proanthocyanidins as a nutritional strategy for mitigating cognitive impairment under thyroxine-induced accelerated aging-like conditions.
Chong Yuan, Na Wang, Kunmiao He et al.· npj Science of Food· 0 citations
Background Alzheimer’s disease (AD)-like cognitive impairment, as a major type of cognitive disorder, has witnessed a sharp rise in prevalence. Therefore, there is an urgent need to develop effective therapeutic intervention measures. Guizhi Fuling Pills (GFP), a classical Traditional Chinese Medicine (TCM) formula, has been shown to exert protective effects on cognitive function. However, its underlying mechanisms remain unclear. Objective To investigate the effects of GFP on AD-like cognitive impairment and elucidate its underlying mechanisms. Methods D-galactose (D-gal)-induced aged mice were used as the model. Mice were administered via gavage for 4 weeks with 0.9% normal saline (0.1 mL/10 g/d), low-dose GFP (12.56 g/kg/d), medium-dose GFP (25.11 g/kg/d), high-dose GFP (50.22 g/kg/d), and donepezil (5 mg/kg/d). A behavioral test was conducted using the Morris water maze. Histopathological changes were observed via H&E staining and immunohistochemistry (IHC). In addition, various methods such as transcriptomics, metabolomics, network pharmacology, and analysis of gut microbiota were utilized to elucidate the possible mechanisms. Results Guizhi Fuling Pills improved learning and memory function in aged mice, ameliorated hippocampal neuronal morphology, and reduced p-Tau protein deposition. Network pharmacology and hippocampal transcriptomic analyses suggested that the active components in GFP may ameliorate cognitive impairment through multiple mechanisms. It included regulation of the VEGF and PI3K/AKT signaling pathways, attenuation of inflammatory responses, inhibition of apoptosis, and repair of the blood-brain barrier (BBB). Gut microbiota analysis revealed that GFP modulated the compositional structure of the gut microbiota, including increasing the abundance of Lactobacillales and decreasing Desulfovibrionia and Tannerellaceae. Metabolomics suggested that GFP may ameliorate metabolic disorders in aged mice by modulating the synthesis of lipids and lipid-like molecules. Conclusion The findings of this study suggest that GFP may ameliorate cognitive dysfunction in AD-like cognitive impairment mice through multiple mechanisms, including repair of the BBB, attenuation of inflammatory responses, and modulation of the gut microbiota and metabolic disorders.
Lan Ma, Jing Wang, Zhenghao Xu et al.· Frontiers in Aging Neuroscie...· 0 citations
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