Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

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discovered genetic linkage to a novel FAD locus on chromosome 12 as well as another putative locus on chromosome 3 (unpublished findings).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

Recent advances in Alzheimer's disease (AD) research were briefly reviewed. The AD affected brain is characterized by numerous amyloid plaques, neurofibrillary tangles, and neuronal losses. The amyloid is composed of amyloid beta peptide (A beta), a 40-42 amino acid fragment of large membrane protein, amyloid precursor protein (APP). A beta is cleaved by proteolytic enzyme, beta, and gamma secretase yielding N and C terminus of the A beta. Considerable effort has been directed to identify these enzymes, and to find the intracellular compartments where A beta is generated. Endosome, lysosomal pathway, or related acidic compartment is one of the candidates for A beta generation. Biochemical and immunopathological data implicate that A beta 42 is more important than A beta 40 in the pathogenesis of AD. On the other hand, many missence mutations in APP gene and other gene, S182 (presenilin1), and STM2 (presenilin2) were identified in familial AD. Neuropathology in these FAD appear basically quite similar, and AD is regarded as cerebral A beta amyloidosis. It was established that missense mutations in the genes encoding APP, presenilin1, and presenilin2, all treated APP processing, leading to increased production of A beta 42. AD amyloid is composed of many other proteins than A beta, designated as amyloid associated proteins, It should be a key issue to determine the precise mechanism, by which A beta is generated, and the alteration of APP trafficking resulting in increased A beta 42 generation with these mutant genes.
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PMID:[Recent advances in Alzheimer's disease research--amyloid precursor protein trafficking, processing, and mutations in Alzheimer's disease linked genes]. 908 57

The genetic associations with the pathological features of AD are diverse: A rapidly growing number of mutations in presenilin 1 and 2 on chromosomes 14 and 1, respectively, are found in many early-onset FAD patients (Lendon et al., 1997). In addition, beta PP mutations are found in a small percentage of early-onset FAD kindreds. The apoE4 allele on chromosome 19 is associated with the presence of the most common form of AD, sporadic AD (Wisniewski & Frangione, 1992; Namba et al., 1991). However, it is clear that other proteins are also involved in the pathogenesis of AD, since some early-onset FAD kindreds do not have linkage to PS1, PS2, apoE, or beta PP, while at least 50% of late-onset AD is unrelated to apoE. Other proteins which have been implicated in the formation of senile plaques, but so far are not known to have any genetic linkage to AD, include proteoglycans (Snow et al., 1987), apoA1 (Wisniewski et al., 1995a), alpha 1-antichymotrypsin (Abraham et al., 1988), HB-GAM (Wisniewski et al., 1996a), complement components (McGeer & Rogers, 1992), acetylcholinesterase (Friede, 1965), and NAC (Ueda et al., 1993). Which of these proteins will be the most important for the etiology of the most common form of AD, late-onset sporadic AD, remains an open question. Three of the genes which are now known to be linked to AD, including PS1, beta PP, and apoE, have been established immunohistochemically and biochemically to be components of senile plaques (see Fig. 1). This raises at least two possibilities: either each of these proteins is part of one pathway with A beta-related amyloid formation as a final causative pathogenic event or amyloid deposition in AD is a reactive process related to dysfunction of a number of different CNS proteins. Whether or not amyloid formation is directly causative in the pathogenesis of AD, current data suggest that new therapeutic approaches which may inhibit the aggregation and/or the conformational change of sA beta to A beta fibrils (Soto et al., 1996) have the greatest likelihood to make a significant impact on controlling amyloid accumulation in AD.
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PMID:Biology of A beta amyloid in Alzheimer's disease. 944 Jan 20

Early-onset familial Alzheimer's disease (early-onset FAD) has been linked with mutations in the presenilin gene, PS1. Mutations in PS1 may affect the processing/trafficking of b-amyloid precursor-protein (bAPP) and favour the production of toxic amyloid-b fragments that are associated with neural degeneration. This study reports the expression of a PS1-like cDNA in the carp (Cyprinus carpio) retina (the encoded protein shows 76% identity to the human PS1 protein). Carp PS1 mRNA was localized by in situ hybridization to the photoreceptor cell, inner nuclear and ganglion cell layers. Expression of the PS1 gene in the rat retina was also confirmed. The retinal expression of PS1 raises the possibility that PS1 mutations also lead to neural degeneration in the retina.
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PMID:Expression and localization in the fish retina of a homologue of the Alzheimer's related PS1 gene. 980 26

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

Early-onset familial Alzheimer's disease (early-onset FAD) has been linked with mutations in the presenilin gene, PS1. Mutations in PS1 may affect the processing/ trafficking of beta-amyloid precursor-protein (betaAPP) and favour the production of toxic amyloid-beta fragments that are associated with neural degeneration. This study reports the expression of a PS1-like cDNA in the carp (Cyprinus carpio) retina (the encoded protein shows 76% identity to the human PS1 protein). Carp PS1 mRNA was localized by in situ hybridization to the photoreceptor cell, inner nuclear and ganglion cell layers. Expression of the PS1 gene in the rat retina was also confirmed. The retinal expression of PS1 raises the possibility that PS1 mutations also lead to neural degeneration in the retina.
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PMID:Expression and localization in the fish retina of a homologue of the Alzheimer's related PS1 gene. 967 92

Alzheimer's disease (AD) is characterized by the invariant accumulation of senile plaques predominantly composed of the pathologically relevant 42-amino acid amyloid beta-peptide (Abeta42). The presenilin (PS) proteins play a key role in Abeta generation. FAD-associated mutations in PS1 and PS2 enhance the production of Abeta42, and PS1 is required for physiological Abeta production, since a gene knockout of PS1 and dominant negative mutations of PS1 abolish Abeta generation. PS proteins undergo endoproteolytic processing, and current evidence indicates that fragment formation may be required for the amyloidogenic function of PS. We have now determined the sequence requirements for endoproteolysis of PS1. Mutagenizing amino acids at the previously determined major cleavage site (amino acid 298) had no effect on PS1 endoproteolysis. In contrast, mutations or deletions at the additional cleavage site around amino acid 292 blocked endoproteolysis. The uncleavable PS1 derivatives accumulated as full-length proteins and replaced the endogenous PS1 proteins. In contrast to the previously described aspartate mutations within transmembrane domains 6 and 7, the uncleaved PS1 variants do not act as dominant negative inhibitors of Abeta production. Moreover, when a FAD-associated mutation (M146L) was combined with a mutation blocking endoproteolysis, Abeta42 production still reached pathological levels. These data therefore demonstrate that endoproteolysis of presenilins is not an absolute prerequisite for the amyloidogenic function of PS1. These data also show that accumulation of the PS1 holoprotein is not associated with the pathological activity of PS1 mutations as suggested previously.
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PMID:Amyloidogenic function of the Alzheimer's disease-associated presenilin 1 in the absence of endoproteolysis. 1054 83

Alzheimer's disease (AD), the most common cause of dementia in the elderly, is a progressive neurodegenerative disorder characterized pathologically by the presence of senile plaques and neurofibrillary tangles in the brains of affected individuals. Senile plaques are composed of amyloid-beta peptides (A beta), a proteolytic derivative of the beta-amyloid precursor protein (beta APP). A subset of AD is inherited as an autosomal dominant trait (familial AD, FAD). Mutations in genes encoding beta APP, presenilin (PS) 1 and PS2 are known to cause FAD. Genetic mutations in all three genes that cosegregate with FAD increase the production of the most amyloidogenic species, A beta 42. Moreover, PS1-deficient neurons exhibit severe defects in the production of A beta, suggesting that PS1 plays an important role in gamma-cleavage that liberates the C terminus of A beta. The physiological role of PS is still unknown, but data from studies in C. elegans, Drosophila and PS1 knock out mice suggests that PS1 plays a crucial role in Notch signaling, and recently it was shown that PS1 is required for the proteolytic release of the intracellular domain of Notch following activation of Notch by its ligand. Further studies on PS-mediated intra- and jaxtamembranous proteolysis will lead to the understanding of the pathological mechanism of AD as well as of a novel mode of membrane protein processing.
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PMID:[Molecular cell biology of presenilins]. 1067 94

We previously reported that overexpression of presenilin 1 and 2 (PS1 and PS2) in HeLa cells leads to cell cycle arrest, and that the PS2(N141I) FAD mutant potentiates cell cycle arrest compared to wild-type PS2. Using similar BrdU incorporation studies we now report that three different PS1 FAD mutants also increase cell cycle arrest compared to wild-type PS1 when overexpressed in either HeLa cells or an ATM deficient cell line. We detected reproducible differences in the degrees to which these FAD mutants induced arrest. PS1(P117L) reduced BrdU incorporation the most (13 to 14%) followed by PS1(P267S) (7.5 to 9%), with the PS1(E280A) mutant inhibiting BrdU incorporation the least (6 to 7%), compared to wild-type PS1. The degree to which the different mutants inhibited cell cycle progression correlates somewhat with the age of AD onset induced by the mutations in carriers. Immunoblot analysis of protein extracts from presenilin-overexpressing cells indicates that the cell cycle-regulated cytoplasmic pool of beta-catenin is dramatically reduced, whereas the insoluble beta-catenin pool remains essentially unaffected. We discuss the implications of these findings in relationship to cell cycle arrest, apoptosis and AD.
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PMID:Familial Alzheimer's disease presenilin-1 mutants potentiate cell cycle arrest. 1112 26

Heterozygous mutations in the genes for amyloid precursor protein (APP), the presenilins (PS1, PS2), prion protein (PrP), neuroserpin, and tau are associated with early-onset dementia (EOD) with or without neurological signs in the early disease stage. To investigate the proportion of EOD without early neurological signs attributable to known genes we prospectively (i.e., ante mortem) screened these six genes for mutations in 36 patients with EOD before age 60. Family history for dementia was positive (PFH) in 16, negative (NFH) in 17, and unknown (UFH) in 3 patients. In 12 patients, we found 5 novel mutations (PS1: F105L; PS2: T122P, M239I; PrP: Q160X, T188K) and 5 previously reported mutations (APP: in three most likely unrelated patients V717I; PS1: A79V, M139V; PrP: P102L, T183A) that all are considered disease causing. Of these 12 patients, 9 had PFH. This indicates a detection rate of 56% (9/16) in patients with PFH. We found 2 mutations (APP V717I) in 2 of the 3 the UFH-patients, and only 1 mutation (PrP T188K) in 1 of the 17 patients with NFH. No mutation was found in tau and neuroserpin genes. To date, three patients died and FAD, predicted by PS mutations in two patients, and prion disease, predicted by a PrP mutation in the third one, were histopathologically confirmed at autopsy. Up to now, mutation findings may be the most specific biomarkers for an ante mortem diagnosis of FAD or hereditary prion disease.
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PMID:High frequency of mutations in four different disease genes in early-onset dementia. 1119 37


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