The Gab2 in signal transduction and its potential role in the pathogenesis of Alzheimer's disease.
Ontology highlight
ABSTRACT:
SUBMITTER: Pan XL
PROVIDER: S-EPMC5560293 | biostudies-other | 2010 Jun
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Insurmountable evidence has demonstrated a strong association between Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA), along with various other cerebrovascular diseases. One form of CAA, which is the accumulation of amyloid-beta peptides (A?) along cerebral vessel walls, impairs perivascular drainage pathways and contributes to cerebrovascular dysfunction in AD. To date, CAA research has been primarily focused on arterial A?, while the accumulation of A? in veins and venules were to a lesser extent. In this review, we describe preclinical models and clinical studies supporting the presence of venular amyloid and potential downstream pathological mechanisms that affect the cerebrovasculature in AD. Venous collagenosis, impaired cerebrovascular pulsatility, and enlarged perivascular spaces are exacerbated by venular amyloid and increase A? deposition, potentially through impaired perivascular clearance. Gaining a comprehensive understanding of the mechanisms involved in venular A? deposition and associated pathologies will give insight to how CAA contributes to AD and its association with AD-related cerebrovascular disease. Lastly, we suggest that special consideration should be made to develop A?-targeted therapeutics that remove vascular amyloid and address cerebrovascular dysfunction in AD.
| S-EPMC7139584 | biostudies-literature
Project description:With the functional demonstration of a role in erythrocyte invasion by Plasmodium falciparum parasites, implications in the aetiology of common conditions that prevail in individuals of African origin, and a wealth of pharmacological knowledge, the stimulatory G protein (Gs) signal transduction pathway presents an exciting target for anti-malarial drug intervention. Having previously demonstrated a role for the G-alpha-s gene, GNAS, in severe malaria disease, we sought to identify other important components of the Gs pathway. Using meta-analysis across case-control and family trio (affected child and parental controls) studies of severe malaria from The Gambia and Malawi, we sought evidence of association in six Gs pathway candidate genes: adenosine receptor 2A (ADORA2A) and 2B (ADORA2B), beta-adrenergic receptor kinase 1 (ADRBK1), adenylyl cyclase 9 (ADCY9), G protein beta subunit 3 (GNB3), and regulator of G protein signalling 2 (RGS2). Our study amassed a total of 2278 cases and 2364 controls. Allele-based models of association were investigated in all genes, and genotype and haplotype-based models were investigated where significant allelic associations were identified. Although no significant associations were observed in the other genes, several were identified in ADORA2A. The most significant association was observed at the rs9624472 locus, where the G allele (approximately 20% frequency) appeared to confer enhanced risk to severe malaria [OR = 1.22 (1.09-1.37); P = 0.001]. Further investigation of the ADORA2A gene region is required to validate the associations identified here, and to identify and functionally characterize the responsible causal variant(s). Our results provide further evidence supporting a role of the Gs signal transduction pathway in the regulation of severe malaria, and request further exploration of this pathway in future studies.
| S-EPMC2850389 | biostudies-literature
Project description:We recently reported that adeno-associated virus serotype 1-constitutively active Ras homolog enriched in brain [AAV1-Rheb(S16H)] transduction of hippocampal neurons could induce neuron-astroglia interactions in the rat hippocampus in vivo, resulting in neuroprotection. However, it remains uncertain whether AAV1-Rheb(S16H) transduction induces neurotrophic effects and preserves the cognitive memory in an animal model of Alzheimer's disease (AD) with characteristic phenotypic features, such as β-amyloid (Aβ) accumulation and cognitive impairments. To assess the therapeutic potential of Rheb(S16H) in AD, we have examined the beneficial effects of AAV1-Rheb(S16H) administration in the 5XFAD mouse model. Rheb(S16H) transduction of hippocampal neurons in the 5XFAD mice increased the levels of neurotrophic signaling molecules, including brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF), and their corresponding receptors, tropomyosin receptor kinase B (TrkB) and CNTF receptor α subunit (CNTFRα), respectively. In addition, Rheb(S16H) transduction inhibited Aβ production and accumulation in the hippocampus of 5XFAD mice and protected the decline of long-term potentiation (LTP), resulting in the prevention of cognitive impairments, which was demonstrated using novel object recognition testing. These results indicate that Rheb(S16H) transduction of hippocampal neurons may have therapeutic potential in AD by inhibiting Aβ accumulation and preserving LTP associated with cognitive memory.
| S-EPMC6947419 | biostudies-literature
Project description:BackgroundAlzheimer's disease (AD) is an extremely complicated neurodegenerative disorder, which accounts for almost 80 % of all dementia diagnoses. Due to the limited treatment efficacy, it is imperative for AD patients to take reliable prevention and diagnosis measures. This study aimed to explore potential biomarkers for AD.MethodsGSE63060 and GSE140829 datasets were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEG) between AD and control groups in GSE63060 were analyzed using the limma software package. The mRNA expression data in GSE140829 was analyzed using weighted gene co-expression network analysis (WGCNA) function package. Protein functional connections and interactions were analyzed using STRING and key genes were screened based on the degree and Maximal Clique Centrality (MCC) algorithm. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on the key genes.ResultsThere were 65 DEGs in GSE63060 dataset between AD patients and healthy controls. In GSE140829 dataset, the turquoise module was related to the pathogenesis of AD, among which, 42 genes were also differentially expressed in GSE63060 dataset. Then 8 genes, RPS17, RPL26, RPS3A, RPS25, EEF1B2, COX7C, HINT1 and SNRPG, were finally screened. Additionally, these 42 genes were significantly enriched in 12 KEGG pathways and 119 GO terms.ConclusionsIn conclusion, RPS17, RPL26, RPS3A, RPS25, EEF1B2, COX7C, HINT1 and SNRPG, were potential biomarkers for pathogenesis of AD, which should be further explored in AD in the future.
| S-EPMC8259215 | biostudies-literature
Project description:Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of age-related dementia that begins with memory loss and progresses to include severe cognitive impairment. A major pathological hallmark of AD is the accumulation of beta amyloid peptide (Aβ) in senile plaques in the brain of AD patients. The exact mechanism by which AD takes place remains unknown. However, an increasing number of studies suggests that ATP-binding cassette (ABC) transporters, which are localized on the surface of brain endothelial cells of the blood-brain barrier (BBB) and brain parenchyma, may contribute to the pathogenesis of AD. Recent studies have unraveled important roles of ABC transporters including ABCB1 (P-glycoprotein, P-gp), ABCG2 (breast cancer resistant protein, BCRP), ABCC1 (multidrug resistance protein 1, MRP1), and the cholesterol transporter ABCA1 in the pathogenesis of AD and Aβ peptides deposition inside the brain. Therefore, understanding the mechanisms by which these transporters contribute to Aβ deposition in the brain is important for the development of new therapeutic strategies against AD. This review summarizes and highlights the accumulating evidence in the literature which describe the role of altered function of various ABC transporters in the pathogenesis and progression of AD and the implications of modulating their functions for the treatment of AD.
| S-EPMC3504479 | biostudies-literature
Project description:Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by irreversible decline in cognition with unclear pathogenesis. Recently, accumulating evidence has revealed that CD2 associated protein (CD2AP), a scaffolding molecule regulates signal transduction and cytoskeletal molecules, is implicated in AD pathogenesis. Several single nucleotide polymorphisms (SNPs) in CD2AP gene are associated with higher risk for AD and mRNA levels of CD2AP are decreased in peripheral lymphocytes of sporadic AD patients. Furthermore, CD2AP loss of function is linked to enhanced Aβ production, Tau-induced neurotoxicity, abnormal neurite structure modulation and reduced blood-brain barrier integrity. This review is to summarize the recent discoveries about the genetics and known functions of CD2AP. The recent evidence concerning the roles of CD2AP in the AD pathogenesis is summarized and CD2AP can be a promising therapeutic target for AD.
| S-EPMC6675523 | biostudies-literature
Project description:Alzheimer's disease (AD), a neurodegenerative disorder associated with advanced age, is the most common cause of dementia globally. AD is characterised by cognitive dysfunction, deposition of amyloid plaques, neurofibrillary tangles and neuro-inflammation. Inflammation of the brain is a key pathological hallmark of AD. Thus, clinical and immunopathological evidence of AD could be potentially supported by inflammatory mediators, including cytokines, chemokines, the complement system, acute phase proteins and oxidative mediators. In particular, oxidative mediators may actively contribute to the progression of AD and on-going inflammation in the brain. This review provides an overview of the functions and activities of inflammatory mediators in AD. An improved understanding of inflammatory processes and their role in AD is needed to improve therapeutic research aims in the field of AD and similar diseases.
| S-EPMC4554263 | biostudies-other
Project description:Background:Alzheimer's Disease (AD) is the most common form of dementia in the elderly. Due to the facts that biological causes of AD are complex in addition to increasing rates of AD worldwide, a deeper understanding of AD etiology is required for AD treatment and diagnosis. Methods:To identify molecular pathological alterations in AD brains, GSE36980 series containing microarray data samples from temporal cortex, frontal cortex and hippocampus were downloaded from Gene Expression Omnibus (GEO) database and valid gene symbols were subjected to building a gene co-expression network by a bioinformatics tool known as differential regulation from differential co-expression (DCGL) software package. Then, a network-driven integrative analysis was performed to find significant genes and underlying biological terms. Results:A total of 17088 unique genes were parsed into three independent differential co-expression networks. As a result, a small number of differentially co-regulated genes mostly in frontal and hippocampus lobs were detected as potential biomarkers related to AD brains. Ultimately differentially co-regulated genes were enriched in biological terms including response to lipid and fatty acid and pathways mainly signaling pathway such as G-protein signaling pathway and glutamate receptor groups II and III. By conducting co-expression analysis, our study identified multiple genes that may play an important role in the pathogenesis of AD. Conclusion:The study aimed to provide a systematic understanding of the potential relationships among these genes and it is hoped that it could aid in AD biomarker discovery.
| S-EPMC6252023 | biostudies-other
Project description:Alzheimer's disease (AD) is an irrevocable neurodegenerative condition characterized by the presence of senile plaques comprising amassed β-amyloid peptides (Aβ) and neurofibrillary tangles mainly comprising extremely phosphorylated Tau proteins. Recent studies have emphasized the role of microRNAs (miRNAs) in the development of AD. A number of miRNAs, namely, miR-200a-3p, miR-195, miR-338-5p, miR-34a-5p, miR-125b-5p, miR-132, miR-384, miR-339-5p, miR-135b, miR-425-5p, and miR-339-5p, have been shown to participate in the development of AD through interacting with BACE1. Other miRNAs might affect the inflammatory responses in the course of AD. Aberrant expression of several miRNAs in the plasma samples of AD subjects has been shown to have the aptitude for differentiation of AD subjects from healthy subjects. Finally, a number of AD-modifying agents affect miRNA profile in cell cultures or animal models. We have performed a comprehensive search and summarized the obtained data about the function of miRNAs in AD in the current review article.
| S-EPMC8005705 | biostudies-literature
Project description:Acinetobacter baumannii is a notorious pathogen in health care settings around the world, primarily due to high resistance to antibiotics. A. baumannii also shows an impressive capability to adapt to harsh conditions in clinical settings, which contributes to its persistence in such conditions. Following their traditional role, the Two Component Systems (TCSs) present in A. baumannii play a crucial role in sensing and adapting to the changing environmental conditions. This provides A. baumannii with a greater chance of survival even in unfavorable conditions. Since all the TCSs characterized to date in A. baumannii play a role in its antibiotic resistance and virulence, understanding the underlying molecular mechanisms behind TCSs can help with a better understanding of the pathways that regulate these phenotypes. This can also guide efforts to target TCSs as novel drug targets. In this review, we discuss the roles of TCSs in A. baumannii, their molecular mechanisms, and most importantly, the potential of using small molecule inhibitors of TCSs as potential novel drug targets.
| S-EPMC6363711 | biostudies-literature