Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: KEGG:D02011 (FAD)
 5,530 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Progressive cerebral deposition of the 39-43-amino-acid amyloid beta-protein (A beta) is an invariant feature of Alzheimer's disease which precedes symptoms of dementia by years or decades. The only specific molecular defects that cause Alzheimer's disease which have been identified so far are missense mutations in the gene encoding the beta-amyloid precursor protein (beta-APP) in certain families with an autosomal dominant form of the disease (familial Alzheimer's disease, or FAD). These mutations are located within or immediately flanking the A beta region of beta-APP, but the mechanism by which they cause the pathological phenotype of early and accelerated A beta deposition is unknown. Here we report that cultured cells which express a beta-APP complementary DNA bearing a double mutation (Lys to Asn at residue 595 plus Met to Leu at position 596) found in a Swedish FAD family produce approximately 6-8-fold more A beta than cells expressing normal beta-APP. The Met 596 to Leu mutation is principally responsible for the increase. These data establish a direct link between a FAD genotype and the clinicopathological phenotype. Further, they confirm the relevance of the continuous A beta production by cultured cells for elucidating the fundamental mechanism of Alzheimer's disease.
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PMID:Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. 146 29

The application of recombinant DNA techniques to AD and DS pathogenesis have provided the molecular biological reagents necessary to delineate the crucial events in the neurodegenerative process in these disorders. Critical issues which remain to be solved include: which form of APP gives rise to beta amyloid deposits and from what cells is it derived? How is APP normally processed and degraded, and does its metabolism differ in various brain regions and cell types in AD and DS patients? Is amyloid toxic to neurons and able to induce NFT formation characteristic of dying neurons or is amyloid simply a secondary by-product of degenerating neurons and nerve terminals in affected regions of AD and DS brain? What is the physical relationship between intracellular amyloid and NFT and how are NFT involved with neuronal cell death? Answers to these questions should elucidate the final events in the degenerative process and provide valuable insights into the basic etiology underlying AD and DS. Meanwhile, isolation and identification of the FAD gene defect on chromosome 21 would provide direct information about the primary cause of FAD. Intensive molecular investigations aimed at deciphering the neuropathogenetic process in AD and DS will hopefully provide valuable biological clues about the primary defect in AD as well as ways to ameliorate the symptoms of both AD and DS.
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PMID:The Alzheimer disease-associated amyloid beta protein precursor gene and familial Alzheimer disease. 212 51

To date, eleven independent FAD pedigrees with the 717Val-->Ile mutation have been identified. Interestingly, five pedigrees were of Japanese origin and four were of British origin. The apparent ethnic prediction of this mutation raises the possibility that there is a founder effect in these two island nations. We did not observe any significant linkage disequilibrium in any locus of APP and GT12 loci in the five Japanese FAD pedigrees with the 717Val-->Ile mutation. A founder effect would probably not be present in Japanese FAD pedgrees with the 717Val-->Ile mutation.
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PMID:Absence of linkage disequilibrium at amyloid precursor protein gene locus in Japanese familial Alzheimer's disease with 717Val-->Ile mutation. 812 39

The early identification of Alzheimer's disease (AD) requires a multifactorial diagnostic approach. Components of a comprehensive assessment include a clinical examination, neuropsychological and psychometric evaluations, biochemical tests, cardiovascular and radiological examinations, neuroimaging, brain bioelectrical activity mapping, an evaluation of brain hemodynamics, and assessment of biological markers. Genetic testing should be incorporated into the diagnostic protocol only for research purposes and risk evaluation. The genetic characterization of familial AD genotypes (FAD-21, FAD-14, FAD-1, FAD-19, APP-21m) can help define the phenotypic profiles of AD clinical subtypes. The correlation of genotypic and phenotypic profiles might have a predictive value in terms of AD diagnosis and therapeutic responses to particular drugs. However, available genetic markers (APP-21m, APO-E) are not yet conclusive for diagnostic purposes. In contrast, AD-related Apo-E genotypes appear to correlate with defined AD phenotypes. The presence of an Apo-E4 allele seems to represent an important risk factor for dementia.
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PMID:Diagnosis of Alzheimer's disease: defining genetic profiles (genotype vs phenotype). 874 Sep 92

A model can be developed for familial APP mutation Alzheimer's disease to explain why a patient who is cognitively normal until middle age experiences a catastrophic amyloid deposition, which is to some extent mirrored in the clinical deterioration due to a subtle shift in A beta metabolism. However, the analysis of young onset dementia hardly constitutes the study of 'the suffering and infirmities of old age' which F E Williams' bequest is intended to promote. It remains to be seen whether the models relevant to APP mutation FAD can be applied to Alzheimer's disease of old age, or indeed other degenerative diseases of later life. Such models, however, do provide an alternative to the view that Alzheimer's disease is an incremental process virtually indistinguishable from old age itself. With an incremental linear process, treatment is akin to a war of attention. By contrast, with a catastrophic process the difference between a normal elderly person and a patient with incipient Alzheimer's disease at the start may be minimal, perhaps only a few molecules of extended A beta peptide, but they diverge very rapidly. If treatment can be directed at the metabolic events at the onset then there is a real opportunity for optimism. If ultimately successful, prevention rather than delay becomes a realistic goal, echoing Duc de La Rochefoucauld's desire 'to die as young as possible as late as possible'.
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PMID:Catastrophe, chaos and Alzheimer's disease. The F E Williams Lecture. 874 13

Four different genes have now been found to contain AD-associated mutations or polymorphisms. While the pathogenic mutations in the early-onset FAD genes, APP, PS1, and PS2 directly cause AD with nearly 100% penetrance, in a larger subset of AD cases with onset over 60 years (maximally for onset at 61-65 years), inheritance of the APOE4 allele confers increased risk for AD but is not sufficient to cause the disease. Together, these four genes appear to account for approximately 50% of FAD cases. We are actively screening the genome for additional FAD loci by genotyping markers in over 400 FAD nuclear pedigrees and affected sib-pairs (83% late-onset and 17% early-onset). We have recently discovered genetic linkage to a novel FAD locus on chromosome 12 as well as another putative locus on chromosome 3 (unpublished findings). Positional cloning strategies are currently under way to identify these potentially novel FAD genes. A common event which is associated with all of the known FAD genes is the excessive accumulation of the A beta peptide and deposition of beta-amyloid in the brain. Thus, a common pathogenic pathway for AD neuropathogenesis appears to center around the cellular trafficking, maturation, and processing of APP, and the subsequent generation, aggregation, and deposition of A beta (or more specifically, A beta 1-42). APP and presenilin gene mutations most likely act as either gain-of-function or dominant negative gene defects which may ultimately lead to the transport of APP into intracellular compartments that promote the enhanced production of A beta or A beta 1-42. AD patients who carry an APOE4 allele experience increased amyloid burden in their brains compared to APOE4-negative AD cases. Thus, the presence of APOE4 would also appear to lead to abnormal generation, aggregation, or clearance of A beta in the brain A beta, perhaps by working in concert with its neuronal receptor, LRP. While the exact mechanisms by which the known FAD gene changes lead to the onset of AD remain unclear, the available data indicate that novel therapies aimed at curbing the generation, aggregation, and deposition of A beta would appear to carry the greatest potential for the effective treatment of this formidable disease.
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PMID:The gene defects responsible for familial Alzheimer's disease. 898 16

The acceptability of presymptomatic testing in 21 people at 50% risk for the APP-692 mutation causing presenile Alzheimer's disease or cerebral haemorrhage resulting from cerebral amyloid angiopathy (FAD-CH), and in 43 people at 50% risk for hereditary Pick disease (HPD) was assessed. Neither group differed in demographic variables. Thirty-nine people (64%) in the whole group would request presymptomatic testing if it were clinically available, although two-thirds did not yet feel ready to take it. The most important reasons in the HPD and FAD-CH group for taking the test were: to further basic research (42% and 47%, respectively), informing children (47% and 50%, respectively), future planning (29% and 47%, respectively), and relieving uncertainty (46% and 27%, respectively). The most commonly cited effect of an unfavourable test result concerned increasing problems for spouses (75% and 76%, respectively) and children (61% and 57%, respectively). Most respondents denied that an unfavourable result would have adverse effects on personal mood or relationship. One-third of all respondents favoured prenatal testing where one of the parents had an increased risk for HPD or FAD-CH. Participants would encourage their offspring to have the test before starting a relationship (35%) and before family planning (44%). Thirty-seven percent of the respondents would encourage their children to opt for prenatal diagnosis. People at risk for HPD were significantly more preoccupied with the occurrence of potential symptoms in themselves, compared with those at risk for FAD-CH, reflecting the devastating impact that disinhibition in the affected patient has on the family. Our findings underline the need for adequate counselling and the availability of professional and community resources to deal with the impact of test results in subjects and their relatives.
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PMID:Preparing for presymptomatic DNA testing for early onset Alzheimer's disease/cerebral haemorrhage and hereditary Pick disease. 903 52

Eleven early-onset dementia families, all with affected individuals who have either presented clinical symptoms of early onset familial Alzheimer's disease (EOFAD) or have been confirmed to have EOFAD by autopsy, and two early onset cases with biopsy-confirmed AD pathology, were screened for missense mutations in the entire coding region of presenilin-1 (PS-1) and -2 (PS-2) genes. Missense mutations were detected by direct sequence analysis of PCR products amplified from genomic DNA templates of affected individuals. Three pedigrees were attributable to known mutations in the PS-1 gene: P264L, E280A and the splice acceptor site (G to T) mutation, which results in the deletion of residues 290-319 of PS-1 (PS-1 delta 290-319). In a fourth pedigree, a novel PS-1 mutation was identified in exon 7 (M233T), which is homologous to a pathogenic PS-2 mutation (M239V), and is characterized by a very early average age of onset (before the age of 35). In one early onset case, another novel PS-1 mutation was identified in exon 8 (R278T). Of the five remaining families and the other early onset case, none have missense mutations in the PS-1 or PS-2 genes, or in exon 16 and 17 of the APP gene. Moreover, two of the PS-1 mutations, PS-1 delta 290-319 and R278T, are associated with the co-presentation of familial spastic paraparesis (FSP) in some of the affected family members. Our data raise the possibility that the phenotypic spectrum associated with PS-1 mutations may extend beyond typical FAD to include FSP, a disease heretofore unsuspected to bear any relationship to FAD. In addition, our data suggest that other novel EOFAD loci, in addition to APP and the presenilin genes, are involved in the aetiology of up to 50% of EOFAD cases.
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PMID:Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. 917 70

The discovery of the PS proteins, the complexities of their biochemistry and their potential involvement in signalling pathways and in apoptosis have galvanized research into AD. To date, the aspect of the functionality of the PSs most relevant to the pathology of AD is the effect of PS FAD mutants to increase the proportion of A beta 42 produced from cells. This, coupled to the observation that gamma-secretase cleavage is considerably reduced in neurons derived from PS-1 knockout mice, argues strongly that PS plays a very direct role in the proteolytic processing of APP.
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PMID:Presenilins--in search of functionality. 976 2

Transgenic animal models are useful in studying the features of APP- and PS1-linked FAD and SOD1-linked FALS. These models help to investigate the nature of the cellular/biochemical/molecular alterations in neural tissue; the character and evolution of neuronal and/or glial abnormalities; the ways mutant proteins cause damage to neurons; and the biochemical pathways associated with cell death. New technologies will help to define changes in a variety of genes/gene products and the events and conformational changes in mutant proteins that are implicated in pathogenic cascades. It is hoped such study will result in novel treatments for testing in transgenic models that can then be translated into new treatments for human neurodegenerative diseases.
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PMID:The value of transgenic models for the study of neurodegenerative diseases. 1119 48


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