Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01034 (cystatin C)
 3,397 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alzheimer's disease (AD) is a genetically complex disorder associated with multiple genetic defects either mutational or of susceptibility. Current AD genetics does not explain in full the etiopathogenesis of AD, suggesting that environmental factors and/or epigenetic phenomena may also contribute to AD pathology and phenotypic expression of dementia. The genomics of AD is still in its infancy, but is helping us to understand novel aspects of the disease including genetic epidemiology, multifactorial risk factors, pathogenic mechanisms associated with genetic networks and genetically-regulated metabolic cascades. AD genomics is also fostering new strategies in pharmacogenomic research and prevention. Functional genomics, proteomics, pharmacogenomics, high-throughput methods, combinatorial chemistry and modern bioinformatics will greatly contribute to accelerating drug development for AD and other complex disorders. The multifactorial genetic dysfunction in AD includes mutational loci (APP, PS1, PS2) and diverse susceptibility loci (APOE, A2M, AACT, LRP1, IL1A, TNF, ACE, BACE, BCHE, CST3, MTHFR, GSK3B, NOS3) distributed across the human genome, probably converging in common pathogenic mechanisms that lead to premature neuronal death. Genomic associations integrate polygenic matrix models to elucidate the genomic organization of AD in comparison to the control population. Using APOE-related monogenic models it has been demonstrated that the therapeutic response to drugs (e.g., cholinesterase inhibitors, non-cholinergic compounds) in AD is genotype-specific. A multifactorial therapy combining three different drugs yielded positive results during 6-12 months in approximately 60% of the patients. With this therapeutic strategy, APOE-4/4 carriers were the worst responders and patients with the APOE-3/4 genotype were the best responders. Other polymorphic variants (PS1, PS2) also influence the therapeutic response to different drugs in AD patients, suggesting that the final pharmacological outcome is the result of multiple genomic interactions, including AD-related genes and genes associated with drug metabolism, disposition, and elimination. The pharmacogenomics of AD may contribute in the future to optimise drug development and therapeutics, increasing efficacy and safety, and reducing side-effects and unnecessary costs.
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PMID:Pharmacogenomics for the treatment of dementia. 1245 80

Alzheimer's disease is a genetically complex disorder associated with multiple genetic defects, either mutational or of susceptibility. Although potentially associated with an accelerated stochastically driven aging process, Alzheimer's disease is an independent clinical entity in which the aging process exerts a deleterious effect on brain activity in conjunction with polymodal genetic factors and other pathological conditions (i.e., age-related cerebrovascular deterioration) and environmental factors (i.e., nutrition). Alzheimer's disease genetics does not explain in full the etiopathogenesis of this disease. Therefore, it is likely that environmental factors and/or epigenetic phenomena also contribute to Alzheimer's disease pathology and phenotypic expression of dementia. The genomics of Alzheimer's disease is still in its infancy, but this field is aiding the understanding of novel aspects of this disease, including genetic epidemiology, multifactorial risk factors, pathogenic mechanisms associated with genetic networks and genetically regulated metabolic cascades. Alzheimer's disease genomics is also helping to develop new strategies in pharmacogenomic research and prevention. Functional genomics, proteomics, pharmacogenomics, high-throughput methods, combinatorial chemistry and modern bioinformatics will greatly contribute to accelerate drug development for Alzheimer's disease and other complex disorders. The multifactorial genetic dysfunction in dementia includes mutational loci (APP, PS1, PS2, TAU) and diverse susceptibility loci (APOE, alpha2M, alphaACT, LRP1, IL1 alpha, TNF, ACE, BACE, BCHE, CST3, MTHFR, GSK3 beta, NOS3 and many other genes) distributed across the human genome, probably converging in a common pathogenic mechanism that leads to premature neuronal death, in which mitochondrial DNA mutations may contribute to increased genetic variability and heterogeneity. In Alzheimer's disease, multiple pathogenic events, including genetic factors, accumulation of aberrant or misfolded proteins, protofibril formation, ubiquitin-proteasome system dysfunction, excitotoxic reactions, oxidative and nitrosative stress, mitochondrial injury, synaptic failure, altered metal homeostasis, dysfunction of axonal and dendritic transport, and chaperone misoperation may converge in pathogenic pathways leading to premature death and neurodegeneration. Some of these mechanisms are common to several neurodegenerative disorders, which differ depending upon the gene(s) affected and the involvement of specific genetic networks, together with epigenetic factors and environmental events. Many genes potentially associated with Alzheimer's disease in some studies cannot be confirmed as candidate genes in replication studies, indicating that methodological problems and genomic complexity are leading to erroneous conclusions. A different approach to Alzheimer's disease functional genomics is to integrate individual genetic information in polygenic genotypes (haplotype-like model) and to investigate genotype-phenotype correlations and genotype-related pharmacogenomic behaviors. The application of functional genomics to Alzheimer's disease can be a suitable strategy for molecular diagnosis and for understanding pathophysiological mechanisms associated with Alzheimer's disease-related neurodegeneration. Furthermore, the pharmacogenomics of Alzheimer's disease may contribute in the future to optimize drug development and therapeutics, increasing efficacy and safety, and reducing side-effects and unnecessary costs.
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PMID:Molecular genetics of Alzheimer's disease and aging. 1647 Feb 48

Genetic factors have a variable impact on Alzheimer's Disease (AD), ranging from familial forms that are transmitted in an autosomal dominant fashion to sporadic AD, where a polygenic component is present. Most genes conferring susceptibility to AD are related to amyloid-beta deposition (APP; PS1; PS2; APOE; Cystatin-C; ubiquilin-1), oxidative stress (NOS2; NOS3) and inflammatory response (IL-1 alpha; IL-1 beta; IL-6; TNF-alpha). Genome-wide analyses, transcriptomics and proteomics approaches have pointed also to proapoptotic genes as increasing AD liability. Depression and psychotic symptoms that occur in a large proportion of AD patients have been associated with monoamine genes coding for metabolic enzymes (COMT), transporters (5-HTTLPR) and receptors (DRD1; DRD3). Genetic testing may be useful to confirm the diagnosis of AD in individuals with clinical signs of dementia, while it is generally not recommended as a predictive testing for AD in asymptomatic individuals. Drugs currently in use to treat AD are effective in only 20% of patients; their therapeutic effect is predominantly under genetic control (CYP26 gene; APOE). Environmental factors have been shown to moderate the effects of genes on psychiatric disorders such as depression, schizophrenia and ADHD. The study of gene-environment interactions in AD, that are still poorly understood, is essential to predict disease-risk in asymptomatic individuals. Genomics will provide a dynamic picture of biological processes in AD and new targets for the forthcoming anti-AD drugs.
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PMID:Genetics of Alzheimer's disease. A rapidly evolving field. 1785 Nov 96

Alzheimer's disease (AD) is a late-onset progressive neurodegenerative disorder which results in the irreversible loss of cortical neurons, particularly in the associative neocortex and hippocampus. AD is the most common form of dementia in the elderly. Apart from the neuronal loss, the pathological hallmarks are extracellular senile plaques, containing the peptide beta-amyloid (Abeta), and neurofibrillary tangles. The Abeta cascade hypothesis remains the main pathogenetic model, as suggested by familiar AD, mainly associated to mutation in amyloid precursor protein and presenilin genes. The remaining 95% of AD patients are mostly sporadic late-onset cases, with a complex aetiology due to interactions between environmental conditions and genetic features of the individual. A relationship between genetic and acquired vascular factors and AD has been hypothesized. Many vascular risk factors for AD, such as atherosclerosis, stroke and cardiac disease in the aging individual, could result in cerebrovascular dysfunction and trigger AD pathology. A major vascular susceptibility factor gene is the apolipoprotein E gene, found to be associated with sporadic late-onset AD cases. Another interesting vascular susceptibility gene is angiotensin converting enzyme. Other possible genes include VLDL-R, LRP, NOS3, CST3, OLR1, MTHFR, PON1 and VEGF, but many of the related studies have shown conflicting results. In this paper, we review the role of molecular vascular abnormalities and of the "vascular risk" genes supposed to be involved in the pathogenesis of AD, in an attempt to provide a comprehensive picture of what is known about the mechanisms underlying the role of vascular factors in late-onset sporadic AD.
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PMID:The role of vascular factors in late-onset sporadic Alzheimer's disease. Genetic and molecular aspects. 1951 4