Physiological β-amyloid clearance by the liver and its therapeutic potential for Alzheimer’s disease

Cheng, Yuan; He, Chenyang; Tian, Ding-Yuan; Chen, Sihan; Ren, Jun-Rong; Sun, Hao‐Lun; Xu, Manyu; Tan, Cheng‐Rong; Fan, Dong-Yu; Jian, Jie-Ming; Sun, Pu‐Yang; Zeng, Guihua; Shen, Yujie; Shi, An-Yu; Jin, Wang-Sheng; Bu, Xian‐Le; Li, Hongming; Xu, Yafang; Wang, Jun; Wang, Yan‐Jiang

doi:10.1007/s00401-023-02559-z

Cited by 24 publications

(17 citation statements)

References 44 publications

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“… 31 Moreover, previous experimental studies have indicated that reduced peripheral Aβ clearance exacerbates Aβ accumulation in the CNS. 32 , 33 Consistent with these studies, we found that reduced peripheral Aβ clearance due to NAFLD was related to cerebral Aβ accumulation, which was negatively correlated with cognitive performance. Therefore, impaired peripheral Aβ clearance serves as a potential explanation for the epidemiological association between NAFLD and cognitive dysfunction.…”

Section: Discussionsupporting

confidence: 87%

“…The liver is the main site of LRP-1 involved in peripheral Aβ clearance, and hepatocyte-specific LRP-1 knockdown has been demonstrated to accelerate cerebral Aβ accumulation and cognitive dysfunction in AD mice. 32 Similarly, we observed diminished hepatic LRP-1 and Aβ uptake in NAFLD, a phenomenon inversely associated with plasma Aβ levels and cerebral Aβ accumulation. Consistently, the positive correlation between NAFLD and plasma Aβ was notably attenuated among individuals carrying the rs1799986 T allele, a subgroup characterized by higher LRP-1 expression compared to carriers of the C allele.…”

Section: Discussionsupporting

confidence: 65%

“…Importantly, previous studies have demonstrated that augmenting hepatic LRP-1 expression through pharmacological intervention or overexpression strategy mitigates cerebral Aβ deposition and enhances cognitive function in AD mice. 32 , 40 Whether enhancing hepatic LRP-1 expression can ameliorate Aβ accumulation and cognitive dysfunction induced by NAFLD warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

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Peripheral amyloid-β clearance mediates cognitive impairment in non-alcoholic fatty liver disease

Peng,

Zhang,

et al. 2024

eBioMedicine

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Peripheral amyloid-β clearance mediates cognitive impairment in non-alcoholic fatty liver disease

Peng,

Zhang,

et al. 2024

eBioMedicine

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“…Interestingly, Cheng et al [ 49 ] found that approximately 13.9% of Aβ42 and 8.9% of Aβ40 were eliminated upon flow through the liver, and this clearance was reduced with the downregulation of the receptor protein for Aβ and recombinant low-density lipoprotein receptor-related protein 1 (LRP1) in the hepatocytes of aged animals. Knocking out the LRP-1 gene reduced the clearing efficiency of Aβ by the liver and exacerbated the Aβ burden and cognitive deficits of the brain while LRP-1 overexpression enhanced the clearing efficiency of Aβ by the liver and attenuated the Aβ deposition in the brain and the cognitive deficits of APP/PS1 mice.…”

Section: Discussionmentioning

confidence: 99%

Treadmill exercise can regulate the redox balance in the livers of APP/PS1 mice and reduce LPS accumulation in their brains through the gut-liver-kupffer cell axis

Yuan,

Wang,

Yang

et al. 2024

Aging

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A growing body of clinical data has shown that patients with Alzheimer’s disease (AD) have symptoms such as liver dysfunction and microbial–gut–brain axis dysfunction in addition to brain pathology, presenting a systemic multisystemic pathogenesis. Considering the systemic benefits of exercise, here, we first observed the effects of long-term treadmill exercise on liver injuries in APP/PS1 transgenic AD mice and explored the potential mechanisms of the gut–liver–brain axis’s role in mediating exercise’s ability to reduce bacterial lipopolysaccharide (LPS) pathology in the brain. The results showed that the livers of the AD mice were in states of oxidative stress, while the mice after long-term treadmill exercise showed alleviation of their oxidative stress, their intestinal barriers were protected, and the ability of their Kupffer cells to hydrolyze LPS was improved, in addition to the accumulation of LPS in their brains being reduced. Notably, the livers of the AD mice were in immunosuppressed states, with lower pro-oxidative and antioxidative levels than the livers of the wild-type mice, while exercise increased both their oxidative and antioxidative levels. These results suggest that long-term exercise modulates hepatic redox homeostasis in AD mice, attenuates oxidative damage, and reduces the accumulation of LPS in the brain through the combined action of the intestine–liver–Kupffer cells.

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“…Recent studies revealed that the contribution of the liver to Aβ clearance and regulation of brain energy metabolic disturbances has attracted interest ( Huang et al, 2022 ). The decline of hepatic Aβ clearance during aging could be involved in AD development, which provides new opportunities for AD treatment ( Cheng et al, 2023 ). These findings implied the possibility of CSS, a well-known formula with the function of soothing liver-qi, ameliorating cognitive deficits through liver modulation.…”

Section: Discussionmentioning

confidence: 99%

Chaihu Shugan San ameliorated cognitive deficits through regulating gut microbiota in senescence-accelerated mouse prone 8

Zeng

et al. 2023

Front. Pharmacol.

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Background: Traditional Chinese medicines exhibit promising preventive effects on Alzheimer’s disease. Chaihu Shugan San (CSS) is a well-known traditional herbal formula whose several kinds of ingredients have the potential of ameliorating Alzheimer’s disease. The present study aimed to evaluate the effects of CSS on the microbiota–gut–brain axis and cognitive deficits of senescence-accelerated mouse prone 8 (SAMP8) mice as well as investigate the underlying mechanisms.Methods: Thirty 5-month-old SAMP8 mice were randomly divided into the model group (SAMP8), CSS low-dose treatment group (CSSL), and CSS high-dose treatment group (CSSH). Ten SAMR1 mice were used as the normal control, and ten SAMP8 mice treated with donepezil were used as the positive control of cognitive function. CSS was orally administrated to SAMP8 mice for 8 weeks. The Morris water maze test was used to evaluate cognitive function. Histological staining was used to observe neuronal injury and Aβ deposition. Transmission electron microscopy was used to observe the synaptic ultrastructure. 16S rRNA gene analysis was performed to measure the changes in intestinal microbiota.Results: The results showed that CSS significantly improved the learning function and memory deficits of aged SAMP8 mice in the Morris water maze examination. CSS ameliorated neuronal injury, synaptic injuries, and Aβ deposition in the brain of SAMP8 mice. In addition, CSS also significantly improved microbiota composition in terms of elevating Lactobacillus reuteri and decreasing Staphylococcus xylosus in the feces of aged SAMP8 mice.Conclusion: These findings suggested that CSS might have a preventive potential for cognitive deficits in aging through regulating gut microbiota, which paved the way for the application of CSS for prevention and therapeutic purposes for mild cognitive impairment as well as Alzheimer’s disease.

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Physiological β-amyloid clearance by the liver and its therapeutic potential for Alzheimer’s disease

Cited by 24 publications

References 44 publications

Peripheral amyloid-β clearance mediates cognitive impairment in non-alcoholic fatty liver disease

Peripheral amyloid-β clearance mediates cognitive impairment in non-alcoholic fatty liver disease

Treadmill exercise can regulate the redox balance in the livers of APP/PS1 mice and reduce LPS accumulation in their brains through the gut-liver-kupffer cell axis

Chaihu Shugan San ameliorated cognitive deficits through regulating gut microbiota in senescence-accelerated mouse prone 8

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