Elevated C-reactive protein mediates the liver-brain axis: a preliminary study

Jiang, Rongtao; Wu, Jing; Rosenblatt, Matthew; Dai, Wei; Rodriguez, Raimundo X.; Sui, Jing; Qi, Shile; Liang, Qinghao; Xu, Bin; Meng, Qingying; Calhoun, Vince D.; Scheinost, Dustin

doi:10.1016/j.ebiom.2023.104679

Cited by 15 publications

(9 citation statements)

References 65 publications

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“…A recent study [ 87 ] involving 447,626 participants reported a significant correlation between liver fibrosis and cognitive function as well as the correlation between liver fibrosis and gray matter volume in various brain regions, including the ventral striatum. Notably, serum C-reactive protein (CRP) in the liver, whose level increases in response to inflammation, also correlated with these two neural parameters, indicating an important role of the liver in brain function.…”

Section: Discussionmentioning

confidence: 99%

Intravenous MSC-Treatment Improves Impaired Brain Functions in the R6/2 Mouse Model of Huntington’s Disease via Recovered Hepatic Pathological Changes

Yu-Taeger,

El-Ayoubi,

et al. 2024

Cells

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Huntington’s disease (HD), a congenital neurodegenerative disorder, extends its pathological damages beyond the nervous system. The systematic manifestation of HD has been extensively described in numerous studies, including dysfunction in peripheral organs and peripheral inflammation. Gut dysbiosis and the gut–liver–brain axis have garnered greater emphasis in neurodegenerative research, and increased plasma levels of pro-inflammatory cytokines have been identified in HD patients and various in vivo models, correlating with disease progression. In the present study, we investigated hepatic pathological markers in the liver of R6/2 mice which convey exon 1 of the human mutant huntingtin gene. Furthermore, we evaluated the impact of intravenously administered Mesenchymal Stromal Cells (MSCs) on the liver enzymes, changes in hepatic inflammatory markers, as well as brain pathology and behavioral deficits in R6/2 mice. Our results revealed altered enzyme expression and increased levels of inflammatory mediators in the liver of R6/2 mice, which were significantly attenuated in the MSC-treated R6/2 mice. Remarkably, neuronal pathology and altered motor activities in the MSC-treated R6/2 mice were significantly ameliorated, despite the absence of MSCs in the postmortem brain. Our data highlight the importance of hepatic pathological changes in HD, providing a potential therapeutic approach. Moreover, the data open new perspectives for the search in blood biomarkers correlating with liver pathology in HD.

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Section: Discussionmentioning

confidence: 99%

Intravenous MSC-Treatment Improves Impaired Brain Functions in the R6/2 Mouse Model of Huntington’s Disease via Recovered Hepatic Pathological Changes

Yu-Taeger,

El-Ayoubi,

et al. 2024

Cells

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“…While limited studies have investigated the impact of aging on hepatic inflammation and function in humans, strong evidence supports the connection between liver and brain-related maladies, as non-alcoholic fatty liver disease has been linked to an increased risk of dementia [55]. A clinical study of over 450,000 participants [56] revealed that males were more likely to experience liver fibrosis and exhibited higher associations between liver fibrosis and most cognitive performance tests, suggesting that hepatic inflammation has a greater neurological impact in males than in females. However, the precise relationship between liver pathology, neuropathology, and neurodegeneration remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Age, Sex and Alzheimer’s disease: A longitudinal study of 3xTg-AD mice reveals sex-specific disease trajectories and inflammatory responses mirrored in postmortem brains from Alzheimer’s patients

Barber,

del Genio,

Swain

et al. 2023

Preprint

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BackgroundAging and sex are major risk factors for developing late-onset Alzheimer’s disease. Compared to men, women are not only nearly twice as likely to develop Alzheimer’s, but they also experience worse neuropathological burden and cognitive decline despite living longer with the disease. It remains unclear how and when sex differences in biological aging emerge and contribute to Alzheimer’s disease pathogenesis. We hypothesized that these differences lead to distinct pathological and molecular Alzheimer’s disease signatures in males and females, which could be harnessed for therapeutic and biomarker development.MethodsWe aged male and female, 3xTg-AD and B6129 (WT) control mice across their respective lifespans while longitudinally collecting brain, liver, spleen, and plasma samples (n=3-8 mice per sex, strain, and age group). We performed histological analyses on all tissues and assessed neuropathological hallmarks of Alzheimer’s disease, markers of hepatic inflammation, as well as splenic mass and morphology. Additionally, we measured concentrations of cytokines, chemokines, and growth factors in the plasma. We conducted RNA sequencing (RNA-Seq) analysis on bulk brain tissue and examined differentially expressed genes (DEGs) between 3xTg-AD and WT samples and across ages in each sex. We also examined DEGs between clinical Alzheimer’s and control parahippocampal gyrus brain tissue samples from the Mount Sinai Brain Bank (MSBB) study in each sex.Results3xTg-AD females significantly outlived 3xTg-AD males and exhibited progressive Alzheimer’s neuropathology, while 3xTg-AD males demonstrated progressive hepatic inflammation, splenomegaly, circulating inflammatory proteins, and next to no Alzheimer’s neuropathological hallmarks. Instead, 3xTg-AD males experienced an accelerated upregulation of immune-related gene expression in the brain relative to females, further suggesting distinct inflammatory disease trajectories between the sexes. Clinical investigations revealed that 3xTg-AD brain aging phenotypes are not an artifact of the animal model, and individuals with Alzheimer’s disease develop similar sex-specific alterations in canonical pathways related to neuronal signaling and immune function. Interestingly, we observed greater upregulation of complement-related gene expression, and lipopolysaccharide (LPS) was predicted as the top upstream regulator of DEGs in diseased males of both species.ConclusionsOur data demonstrate that chronic inflammation and complement activation are associated with increased mortality, revealing that age-related changes in immune response act as a primary driver of sex differences in Alzheimer’s disease trajectories. We propose a model of disease pathogenesis in 3xTg-AD males in which aging and transgene-driven disease progression trigger an inflammatory response, mimicking the effects of LPS stimulation despite the absence of infection.

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“…Recent studies have shown that the progression of chronic liver diseases, such as liver fibrosis and non-alcoholic fatty liver disease (NAFLD), is associated with cognitive decline and structural changes in the brain ( Merli et al, 2013 ; Leone et al, 2023 ). Abnormal liver function may contribute to increased levels of peripheral inflammatory responses and decreased clearance of harmful substances such as Aβ ( Wiest et al, 2021 ; Jiang R. et al, 2023 ). The mitigation of neurocognitive impairments may be exerted by treatment of the primary disease (e.g., NAFLD and hepatic fibrosis) or compensatory measures of liver function (e.g., albumin infusion) ( Cheon and Song, 2022 ; Fagan et al, 2023 ).…”

Section: Prevention and Treatment Strategies Based On Peripheral Infl...mentioning

confidence: 99%

Peripheral inflammation and neurocognitive impairment: correlations, underlying mechanisms, and therapeutic implications

Tan,

Chen,

Kong

et al. 2023

Front. Aging Neurosci.

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Cognitive impairments, such as learning and memory deficits, may occur in susceptible populations including the elderly and patients who are chronically ill or have experienced stressful events, including surgery, infection, and trauma. Accumulating lines of evidence suggested that peripheral inflammation featured by the recruitment of peripheral immune cells and the release of pro-inflammatory cytokines may be activated during aging and these conditions, participating in peripheral immune system-brain communication. Lots of progress has been achieved in deciphering the core bridging mechanism connecting peripheral inflammation and cognitive impairments, which may be helpful in developing early diagnosis, prognosis evaluation, and prevention methods based on peripheral blood circulation system sampling and intervention. In this review, we summarized the evolving evidence on the prevalence of peripheral inflammation-associated neurocognitive impairments and discussed the research advances in the underlying mechanisms. We also highlighted the prevention and treatment strategies against peripheral inflammation-associated cognitive dysfunction.

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Elevated C-reactive protein mediates the liver-brain axis: a preliminary study

Cited by 15 publications

References 65 publications

Intravenous MSC-Treatment Improves Impaired Brain Functions in the R6/2 Mouse Model of Huntington’s Disease via Recovered Hepatic Pathological Changes

Intravenous MSC-Treatment Improves Impaired Brain Functions in the R6/2 Mouse Model of Huntington’s Disease via Recovered Hepatic Pathological Changes

Age, Sex and Alzheimer’s disease: A longitudinal study of 3xTg-AD mice reveals sex-specific disease trajectories and inflammatory responses mirrored in postmortem brains from Alzheimer’s patients

Peripheral inflammation and neurocognitive impairment: correlations, underlying mechanisms, and therapeutic implications

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