Effect and Mechanism of Rapamycin on Cognitive Deficits in Animal Models of Alzheimer's Disease: A Systematic Review and Meta-analysis of Preclinical Studies.

Background: Alzheimer's disease (AD), the most common form of dementia, remains long-term and challenging to diagnose. Furthermore, there is currently no medication to completely cure AD patients. Rapamycin has been clinically demonstrated to postpone the aging process in mice and improve learning and memory abilities in animal models of AD. Therefore, rapamycin has the potential to be significant in the discovery and development of drugs for AD patients. Objective: The main objective of this systematic review and meta-analysis was to investigate the effects and mechanisms of rapamycin on animal models of AD by examining behavioral indicators and pathological features. Methods: Six databases were searched and 4,277 articles were retrieved. In conclusion, 13 studies were included according to predefined criteria. Three authors independently judged the selected literature and methodological quality. Use of subgroup analyses to explore potential mechanistic effects of rapamycin interventions: animal models of AD, specific types of transgenic animal models, dosage, and periodicity of administration. Results: The results of Morris Water Maze (MWM) behavioral test showed that escape latency was shortened by 15.60 seconds with rapamycin therapy, indicating that learning ability was enhanced in AD mice; and the number of traversed platforms was increased by 1.53 times, indicating that the improved memory ability significantly corrected the memory deficits. CONCLUSIONS: Rapamycin therapy reduced age-related plaque deposition by decreasing AßPP production and down-regulating ß-secretase and γ-secretase activities, furthermore increased amyloid-ß clearance by promoting autophagy, as well as reduced tau hyperphosphorylation by up-regulating insulin-degrading enzyme levels.

Knowledge domains and emerging trends of Genome-wide association studies in Alzheimer's disease: A bibliometric analysis and visualization study from 2002 to 2022.

OBJECTIVES: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive decline in cognitive and behavioral function. Studies have shown that genetic factors are one of the main causes of AD risk. genome-wide association study (GWAS), as a novel and effective tool for studying the genetic risk of diseases, has attracted attention from researchers in recent years and a large number of studies have been conducted. This study aims to summarize the literature on GWAS in AD by bibliometric methods, analyze the current status, research hotspots and future trends in this field. METHODS: We retrieved articles on GWAS in AD published between 2002 and 2022 from Web of Science. CiteSpace and VOSviewer software were applied to analyze the articles for the number of articles published, countries/regions and institutions of publication, authors and cited authors, highly cited literature, and research hotspots. RESULTS: We retrieved a total of 2,751 articles. The United States had the highest number of publications in this field, and Columbia University was the institution with the most published articles. The identification of AD-related susceptibility genes and their effects on AD is one of the current research hotspots. Numerous risk genes have been identified, among which APOE, CLU, CD2AP, CD33, EPHA1, PICALM, CR1, ABCA7 and TREM2 are the current genes of interest. In addition, risk prediction for AD and research on other related diseases are also popular research directions in this field. CONCLUSION: This study conducted a comprehensive analysis of GWAS in AD and identified the current research hotspots and research trends. In addition, we also pointed out the shortcomings of current research and suggested future research directions. This study can provide researchers with information about the knowledge structure and emerging trends in the field of GWAS in AD and provide guidance for future research.

Effect and Potential Mechanism of Immunotherapy on Cognitive Deficits in Animal Models of Alzheimer's Disease: A Systematic Review and Meta-Analysis.

OBJECTIVE: Immunotherapy has been reported to ameliorate Alzheimer's disease (AD) in the animal model; however, the immunologic approaches and mechanisms have not been specifically described. Thus, the systematic review and meta-analysis were conducted to explore the effect and potential mechanism of immunotherapy on AD animal experiments based on behavioral indicators. METHODS: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Cochrane Collaboration guidelines and the inclusion/exclusion criteria of immunotherapy in animal studies, 15 studies were systematically reviewed after extraction from a collected database of 3,742 publications. Finally, the effect and mechanism of immunotherapy on AD models were described by performing multiple subgroup analyses. RESULTS: After immunotherapy, the escape latency was reduced by 18.15 seconds and the number of crossings over the platform location was increased by 1.60 times in the Morris Water Maze. Furthermore, compared to the control group, active and passive immunization could markedly ameliorate learning and memory impairment in 3 × Tg AD animal models, and active immunization could ameliorate the learning and memory ability of the APPswe/PS1ΔE9 AD animal model. Meanwhile, it could be speculated that cognitive dysfunction was improved by immunotherapy, perhaps mainly via reducing Aß40, Aß42, and Tau levels, as well as increasing IL-4 levels. CONCLUSION: Immunotherapy significantly ameliorated the cognitive dysfunction of AD animal models by assessing behavioral indicators.

Glucagon-like peptide 1 (GLP-1) receptor agonists in experimental Alzheimer's disease models: a systematic review and meta-analysis of preclinical studies.

Alzheimer's disease (AD) is a degenerative disease of the nervous system. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), a drug used to treat type 2 diabetes, have been shown to have neuroprotective effects. This systematic review and meta-analysis evaluated the effects and potential mechanisms of GLP-1 RAs in AD animal models. 26 studies were included by searching relevant studies from seven databases according to a predefined search strategy and inclusion criteria. Methodological quality was assessed using SYRCLE's risk of bias tool, and statistical analysis was performed using ReviewManger 5.3. The results showed that, in terms of behavioral tests, GLP-1 RAs could improve the learning and memory abilities of AD rodents; in terms of pathology, GLP-1 RAs could reduce Aß deposition and phosphorylated tau levels in the brains of AD rodents. The therapeutic potential of GLP-1 RAs in AD involves a range of mechanisms that work synergistically to enhance the alleviation of various pathological manifestations associated with the condition. A total of five clinical trials were retrieved from ClinicalTrials.gov. More large-scale and high-quality preclinical trials should be conducted to more accurately assess the therapeutic effects of GLP-1 RAs on AD.

Effects of hyperhomocysteinemia on ischemic cerebral small vessel disease and analysis of inflammatory mechanisms.

Purpose: Hyperhomocysteinemia is closely related to, but is not a confirmed risk factor of, cerebral small vessel disease (CSVD). This study aimed to determine whether hyperhomo-cysteinemia is correlated significantly with CSVD.Materials and methods: This cross-sectional study compared the homocysteine (Hcy) levels of patients with and without CSVD. High-sensitivity C-reactive protein (hs-CRP) levels were compared according to white matter lesion (WML) severity, which was classified using the Fazekas system. Risk factors for ischemic CSVD were analyzed through multivariate unconditional logistic regression analysis.Results: Hcy levels were significantly higher in patients with lacunar infarction (LI) than in controls (p=.0438), in patients with Fazekas 2-3 than in patients with Fazekas 0-1 WMLs (p=.0192), in patients with Fazekas 4-6 than in patients with Fazekas 2-3 WMLs (p=.0207), and in patients with LI than in patients without LI (p=.0043). hs-CRP levels were significantly higher in patients with LI than in patients without LI (p=.0068) and in patients with Fazekas 4-6 than in patients with Fazekas 0-1 WMLs (p=.0031). Three multivariate unconditional logistic regression analyses showed that hyperhomocysteinemia is a risk factor for LI (p=.006; odds ratio [OR], 27.668), severe WML (p=.028; OR, 1.984), and high hs-CRP level (p=.016; OR, 3.956).Conclusions: The assessment of Hcy levels is important for ischemic CSVD. Hyperhomocysteinemia is a risk factor for LI and severe WML. Further, hyperhomocysteinemia is associated with high hs-CRP levels, and this may involve an inflammatory mechanism; however, further studies are needed in this regard.

Study of the Inflammatory Mechanisms in Hyperhomocysteinemia on Large-Artery Atherosclerosis Based on Hypersensitive C-Reactive Protein-A Study from Southern China.

OBJECTIVE: To study the inflammatory mechanism of hyperhomocysteinemia on large-artery atherosclerosis based on hypersensitive C-reactive protein in patients. METHODS: In all, 153 inpatients and 1357 physical examinees were selected. The levels of homocysteine were compared between the carotid/intracranial artery stenosis group and the nonstenosis group, between the carotid artery unstable plaque group and the nonplaque group, and between the intima-media thickness (IMT) greater than or equal to 1 group and the normal IMT group. The hypersensitive C-reactive protein levels were compared between the lacunar infarction (LI) group and the nonstroke control group and between the unstable plaque group and the nonplaque group. RESULTS: Homocysteine level was significantly higher in the carotid/intracranial artery stenosis group than in the nonstenosis group, in the LI group than in the inpatient nonstroke group, and in the IMT greater than or equal to 1 group than in the normal IMT group. The hypersensitive C-reactive protein level was significantly higher in the LI group than in the nonstroke group and in the unstable plaque group than in the nonplaque group. CONCLUSIONS: Hyperhomocysteinemia may aggravate the development of IMT, carotid atherosclerotic plaque instability, and carotid/intracranial artery stenosis by increasing inflammation, ultimately leading to the occurrence of LI. Hyperhomocysteinemia-induced inflammation mechanism warrants further study.

[Effect of plasma fibrinogen level-based defibrase therapy in patients with acute cerebral infarction].

OBJECTIVE: To evaluate the therapeutic effect of individualized defibrase therapy according to the level of plasma fibrinogen (FIB) in patients with acute cerebral infarction (ACI). METHODS: Sixty patients with ACI (within 72 h after onset) were randomly divided into defibrase group (n=30) and control group (n=30). The patients in defibrase group received intravenous defibrase infusion at different first doses (15, 10, and 5 U) according to plasma FIB level (>4 g/L, 2-4 g/L, and 1.3-2 g/L) before treatment. Plasma FIB was measured every 12 h after the first dose of defibrase, and when plasma FIB was over 1.3 g/L, intravenous infusion of 5 U defibrase was given to maintain plasma FIB within the range of 0.70-1.13 g/L over a period of 7 days. The plasma prothrombin time (PT), activated partial thromboplastin time (APTT) and FIB before and after the 7-day treatment were measured, and the scores of Chinese stroke scale (CSS) after 14 days of treatment and Activity of Daily Living (ADL) after 3 months were recorded. RESULTS: After 7 days of treatment, plasma PT and APTT were significantly prolonged lengthened and plasma FIB was lowered in defibrase group. The scores of CSS improved in defibrase group after 14 days of treatment, showing significant difference from those of the control group. The clinical effective rate was 80% in defibrase group, significantly higher than that in the control group (50%). The scores of ADL after 3 months were similar between the 2 groups, but the percentage of independent living and mild dependency was significantly higher in defibrase group (93.3% vs 70.0%). No intracerebral and extracerebral hemorrhage occurred in defibrase group the during treatment, no did death occur after 3 months of treatment. CONCLUSION: Defibrase therapy based on plasma FIB level can rapidly and effectively lower plasma FIB, reduce neurological impairment and improve the quality of life in patients with ACI.

Genetic analysis of interleukin-1A C(-889)T polymorphism with Alzheimer disease.

Neuroinflammation has been implicated in the etiology of Alzheimer's disease (AD). Many studies have suggested that C(-889) T promoter polymorphism in one of the proinflammatory cytokine interleukin-1 (IL-1) encoding gene IL-1A may be associated with AD pathogenesis. To determine whether the polymorphism contributes to the risk for late-onset AD (LOAD) in Chinese, we carried out our investigation in 344 sporadic LOAD patients and 224 healthy controls. No statistical significant association was obtained between IL-1A C(-889) T polymorphism and LOAD and no statistical difference was found between cases and controls after stratification for apolipoprotein E allele 4 (APOE epsilon4) status. The results reveal that it is not likely that the IL-1A C(-889) T polymorphism is involved in AD pathogenesis in the Chinese population. Further studies of the associations between other IL-1A genetic polymorphisms and AD should be performed in a larger population and biologic functional analysis of IL-1A gene is required to verify the underlying roles of IL-IA in LOAD.