Trillions of intestinal bacteria in the human body undergo dynamic transformations in response to physiological and pathological changes. Alterations in their composition and metabolites collectively ...contribute to the progression of Alzheimer's disease. The role of gut microbiota in Alzheimer's disease is diverse and complex, evidence suggests lipid metabolism may be one of the potential pathways. However, the mechanisms that gut microbiota mediate lipid metabolism in Alzheimer's disease pathology remain unclear, necessitating further investigation for clarification. This review highlights the current understanding of how gut microbiota disrupts lipid metabolism and discusses the implications of these discoveries in guiding strategies for the prevention or treatment of Alzheimer's disease based on existing data.
Significance Alzheimer’s disease (AD) is a devastating disease that results in the progressive cognitive deficits of elderly and has become one of major social and economic burdens worldwide. There ...is no effective drug or therapy to prevent or halt the progressive cognitive dysfunctions due to the complex mechanisms such as accumulation of amyloid-β (Aβ), increase in oxidative stress, and formation of neurofibrillary tangle that drive the development of the disease. We found here that Edaravone, a drug that has been used for ischemic stroke, is able to prevent and treat AD by targeting multiple pathways of AD pathogenesis and rescuing the cognitive deficits of a mouse model of AD. Our study suggests Edaravone is a promising drug candidate for AD.
Alzheimer’s disease (AD) is one of most devastating diseases affecting elderly people. Amyloid-β (Aβ) accumulation and the downstream pathological events such as oxidative stress play critical roles in pathogenesis of AD. Lessons from failures of current clinical trials suggest that targeting multiple key pathways of the AD pathogenesis is necessary to halt the disease progression. Here we show that Edaravone, a free radical scavenger that is marketed for acute ischemic stroke, has a potent capacity of inhibiting Aβ aggregation and attenuating Aβ-induced oxidation in vitro. When given before or after the onset of Aβ deposition via i.p. injection, Edaravone substantially reduces Aβ deposition, alleviates oxidative stress, attenuates the downstream pathologies including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, synaptic dysfunction, and rescues the behavioral deficits of APPswe/PS1 mice. Oral administration of Edaravone also ameliorates the AD-like pathologies and memory deficits of the mice. These findings suggest that Edaravone holds a promise as a therapeutic agent for AD by targeting multiple key pathways of the disease pathogenesis.
Amyloid-beta (Aβ) plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD). Clearance of Aβ is a promising therapeutic strategy for AD. We have previously demonstrated that peripheral ...organs play important roles in the clearance of brain-derived Aβ. In the present study, we recruited 46 patients with liver cirrhosis and 46 normal controls and found that plasma Aβ40 and Aβ42 levels were significantly higher in the cirrhosis patients than in the normal controls. Notably, cirrhosis patients with hepatitis B virus (HBV) infection had higher plasma Aβ40 and Aβ42 levels than HBV-negative cirrhosis patients. Besides, cirrhosis patients had significantly higher plasma levels of interleukin-1β (IL-1β) and IL-6. Plasma tumor necrosis factor α (TNF-α) and interferon-γ (IFN-γ) levels were not significantly different between the groups. Moreover, we found significant correlations of hepatic functions with plasma Aβ40 and Aβ42 levels. Plasma IL-6 levels were also significantly correlated with plasma Aβ40 levels. However, in the linear regression model, we found significant correlation of plasma Aβ40 levels with hepatic functions, but not with plasma IL-6 levels. Our results indicate that the hepatic dysfunctions might result in decreased peripheral Aβ clearance by the liver. Protecting hepatic functions might be helpful for the clearance of brain-derived Aβ in the blood.
Alzheimer’s disease (AD), the most common type of dementia, is becoming a major challenge for global health and social care. However, the current understanding of AD pathogenesis is limited, and no ...early diagnosis and disease-modifying therapy are currently available. During the past year, significant progress has been made in clinical research on the diagnosis, prevention, and treatment of AD. In this review, we summarize the latest achievements, including diagnostic biomarkers, polygenic hazard score, amyloid and tau PET imaging, clinical trials targeting amyloid-beta (Aβ), tau, and neurotransmitters, early intervention, and primary prevention and systemic intervention approaches, and provide novel perspectives for further efforts to understand and cure the disease.
Reactive oxygen species formed within the mammalian cell can produce 8-oxo-7,8-dihydroguanine (8-oxoG) in mRNA, which can cause base mispairing during gene expression. Here we found that ...administration of 8-oxoGTP in MTH1-knockdown cells results in increased 8-oxoG content in mRNA. Under this condition, an amber mutation of the reporter luciferase is suppressed. Using secondgeneration sequencing techniques, we found that U-to-G changes at preassigned sites of the luciferase transcript increased when 8-oxoGTP was supplied. In addition, an increased level of 8-oxoG content in RNA induced the accumulation of aggregable amyloid β peptides in cells expressing amyloid precursor protein. Our findings indicate that 8-oxoG accumulation in mRNA can alter protein synthesis in mammalian cells. Further work is required to assess the significance of these findings under normal physiological conditions.
Exercise elicits a wide range of physiological responses in mammalian tissues that enhance a broad range of functions, particularly in improving cognitive performance. However, the field lacks a ...comprehensive bibliometric analysis that clarifies its knowledge structure and research hotspots. This study aims to address this gap and map the research landscape regarding the role of exercise in cognitive function enhancement. Firstly, the frequencies and co-occurrence of keywords were analysed to identify six main clusters: aging, cognitive impairment, rehabilitation, obesity, fatigue, and hippocampus. Secondly, reference timeline co-citation analysis revealed that hippocampus and aging were the major bursts with high intensity and long attention span while children had recently emerged as a topical subject. Finally, the evolution of themes from 2012 to 2022 was analysed, and found that older adults had been the leading research theme for exercise affecting cognition. Childhood obesity was an emerging theme that attracted increasing research attention in recent years while the hippocampus research theme expanded rapidly during the decade but remained a niche topic with less relevance to others. This research identified and summarised research priorities and evolutionary trends in exercise to improve cognition by constructing knowledge networks through visual analysis. It provides researchers with a comprehensive insight into the current state of the field to facilitate further research.
The neurotrophin receptor p75 (p75NTR) is a receptor for amyloid‐beta (Aβ) and mediates Aβ‐induced neurodegenerative signals. The ectodomain of p75NTR (p75ECD) is a physiological protective factor ...against Aβ in Alzheimer's disease (AD). We have previously demonstrated that the shedding of p75ECD from the cell surface is down‐regulated in AD brains and restoration of the p75ECD level in the brain, through intracranial administration of p75ECD by adeno‐associated virus vectors, attenuates AD‐like pathologies in an AD mouse model. In this study, we further investigated the feasibility and efficacy of peripheral administration of AAV‐p75ECD on brain amyloid burden and associated pathogenesis. We found that intramuscular delivery of AAV‐p75ECD increased the level of p75ECD in the blood, significantly improved the behavioral phenotype of amyloid precursor protein/PS1 transgenic mice, and reduced brain amyloid burden, attenuated Tau hyperphosphorylation, and neuroinflammation. Furthermore, intramuscular delivery of AAV‐p75ECD was well tolerated. Our results indicate that peripheral delivery of p75ECD represents a safe and effective therapeutic strategy for AD.
The ectodomain of p75NTR (p75ECD) is a physiological protective factor against amyloid‐beta (Aβ) in Alzheimer's disease (AD). Intramuscular delivery of AAV‐p75ECD increased the p75ECD levels in the blood, reduced brain amyloid burden through a ‘peripheral sink’ mechanism and alleviates AD‐type pathologies. Peripheral delivery of p75ECD represents a promising therapeutic strategy for AD.
The ectodomain of p75NTR (p75ECD) is a physiological protective factor against amyloid‐beta (Aβ) in Alzheimer's disease (AD). Intramuscular delivery of AAV‐p75ECD increased the p75ECD levels in the blood, reduced brain amyloid burden through a ‘peripheral sink’ mechanism and alleviates AD‐type pathologies. Peripheral delivery of p75ECD represents a promising therapeutic strategy for AD.
Neurofibrillary tangles of hyperphosphorylated tau protein (p-tau) are a key pathological feature of Alzheimer's disease (AD). Tau phosphorylation is suggested to be secondary to amyloid-beta (Aβ) ...accumulation. However, the mechanism by which Aβ induces tau phosphorylation in neurons remains unclear. Neurotrophin receptor p75 (p75NTR) is a receptor for Aβ and mediates Aβ neurotoxicity, implying that p75NTR may mediate Aβ-induced tau phosphorylation in AD. Here, we showed that Aβ-induced tau hyperphosphorylation and neurodegeneration, including tau phosphorylation, synaptic disorder and neuronal loss, in the brains of both male wild-type (Wt) mice and male P301L transgenic mice (a mouse model of human tauopathy) were alleviated by genetic knockout of p75NTR in the both mouse models. We further confirmed that the activation or inhibition of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase-3β (GSK3β) significantly changed Aβ/p75NTR-mediated p-tau levels in neurons. Treatment of male P301L mice with soluble p75NTR extracellular domain (p75ECD-Fc), which antagonizes the binding of Aβ to p75NTR, suppressed tau hyperphosphorylation. Taken together, our findings suggest that p75NTR meditates Aβ-induced tau pathology and is a potential druggable target for AD and other tauopathies.
•p75NTR mediates Aβ-induced neuronal tau hyperphosphorylation.•The calpain/CDK5 and AKT/GSK3β pathways are involved in Aβ/p75NTR-induced tau hyperphosphorylation.•Modulation of p75NTR is a potential therapeutic approach to rescue brain tau pathology in AD.
Tau pathology is characterized as a form of frontotemporal lobar degeneration (FTLD) known as FTLD-tau. The underlying pathogenic mechanisms are not known and no therapeutic interventions are ...currently available. Here, we report that the neurotrophin receptor p75NTR plays a critical role in the pathogenesis of FTLD-tau. The expression of p75NTR and the precursor of nerve growth factor (proNGF) were increased in the brains of FTLD-tau patients and mice (P301L transgenic). ProNGF-induced tau phosphorylation via p75NTR in vitro, which was associated with the AKT/glycogen synthase kinase (GSK)3β pathway. Genetic reduction of p75NTR in P301L mice rescued the memory deficits, alleviated tau hyperphosphorylation and restored the activity of the AKT/GSK3β pathway. Treatment of the P301L mice with the soluble p75NTR extracellular domain (p75ECD-Fc), which can antagonize neurotoxic ligands of p75NTR, effectively improved memory behavior and suppressed tau pathology. This suggests that p75NTR plays a crucial role in tau paGSKthology and represents a potential druggable target for FTLD-tau and related tauopathies.
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