Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The amyloidogenesis occurring in Alzheimer's disease represents a fundamental membrane-related pathology involving a membrane-bound substrate metabolized by integral membrane proteases (secretases). Thus, the amyloid-beta peptide (Abeta), which accumulates extracellularly as plaques in the brains of Alzheimer's disease patients, is derived by sequential proteolytic cleavage of the integral transmembrane amyloid precursor protein (APP). Beta-Secretase or BACE-1 (beta-site APP cleaving enzyme) is a transmembrane aspartic protease responsible for the first of these cleavage events, generating the soluble APP ectodomain sAPPbeta, and a C-terminal fragment CTFbeta. CTFbeta is subsequently cleaved by the ?gamma-secretase complex, of which presenilin is the catalytic core, to produce Ass. A variety of studies indicate that cholesterol is an important factor in the regulation of Ass production, with high cholesterol levels being linked to increased Ass generation and deposition. However, the mechanism(s) underlying this effect are unclear at present. Recent evidence suggests that amyloidogenic APP processing may preferentially occur in the cholesterol-rich regions of membranes known as lipid rafts, and that changes in cholesterol levels could exert their effects by altering the distribution of APP-cleaving enzymes within the membrane. Rafts may be involved in the aggregation of Ass and also in its clearance by amyloid-degrading enzymes such as plasmin or possibly neprilysin (NEP).
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PMID:The involvement of lipid rafts in Alzheimer's disease. 1661 86

Traumatic brain injury (TBI) is a risk factor for developing Alzheimer's disease (AD). Additionally, TBI induces AD-like amyloid beta (Abeta) plaque pathology within days of injury potentially resulting from massive accumulation of amyloid precursor protein (APP) in damaged axons. Here, progression of Abeta accumulation was examined using brain tissue from 23 cases with post-TBI survival of up to 3 years. Even years after injury, widespread axonal pathology was consistently observed and was accompanied by intra-axonal co-accumulations of APP with its cleavage enzymes, beta-site APP cleaving enzyme and presenilin-1 and their product, Abeta. However, in marked contrast to the plaque pathology noted in short-term cases post TBI, virtually no Abeta plaques were found in long-term survivors. A potential mechanism for Abeta plaque regression was suggested by the post-injury accumulation of an Abeta degrading enzyme, neprilysin. These findings fail to support the premise that progressive plaque pathology after TBI ultimately results in AD.
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PMID:A lack of amyloid beta plaques despite persistent accumulation of amyloid beta in axons of long-term survivors of traumatic brain injury. 1849 93

Alzheimer's disease (AD) is the major cause of dementia in the elderly, leading to memory loss and cognitive decline. The mechanism underlying onset of the disease has not been fully elucidated. However, characteristic pathological manifestations include extracellular accumulation and aggregation of the amyloid beta-peptide (Abeta) into plaques and intracellular accumulation and aggregation of hyperphosphorylated tau, forming neurofibrillary tangles. Despite extensive research worldwide, no disease modifying treatment is yet available. In this review, we focus on gene therapy as a potential treatment for AD, and summarize recent work in the field, ranging from proof-of-concept studies in animal models to clinical trials. The multifactorial causes of AD offer a variety of possible targets for gene therapy, including two neurotrophic growth factors, nerve growth factor and brain-derived neurotrophic factor, Abeta-degrading enzymes, such as neprilysin, endothelin-converting enzyme and cathepsin B, and AD associated apolipoprotein E. This review also discusses advantages and drawbacks of various rapidly developing virus-mediated gene delivery techniques for gene therapy. Finally, approaches aiming at down-regulating amyloid precursor protein (APP) and beta-site APP cleaving enzyme 1 levels by means of siRNA-mediated knockdown are briefly summarized. Overall, the prospects appear hopeful that gene therapy has the potential to be a disease modifying treatment for AD.
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PMID:Gene therapy in Alzheimer's disease - potential for disease modification. 2015 67