Mapping of a gene predisposing to early–onset Alzheimer's disease to chromosome 14q24.3

Broeckhoven, Christine Van; Backhovens, Hubert; Cruts, Marc; Winter, G. De; Bruyland, M.; Cras, Patrick; Martin, J. J.

doi:10.1038/ng1292-335

Cited by 294 publications

(101 citation statements)

References 26 publications

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“…9 Since then, a number of important breakthroughs have been made, particularly the linkage of genetic mutations with familial, early-onset forms of AD, most of which are associated with an increased ratio of Ab1-42/1-40 or an increased total production of Ab. 6,[10][11][12][13][14][15][16][17][18][19][20] However, early-onset forms of AD only appear to account for a small proportion of total AD cases. The vast majority may result from deficiencies in the ability of the brain to clear Ab.…”

Section: Introductionmentioning

confidence: 99%

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

et al. 2008

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Currently, the 'amyloid hypothesis' is the most widely accepted explanation for the pathogenesis of Alzheimer's disease (AD). According to this hypothesis, altered metabolism of the amyloid-b (Ab) peptide is central to the pathological cascade involved in the pathogenesis of AD. Although Ab is produced by almost every cell in the body, a physiological function for the peptide has not been determined, and the pathways by which Ab leads to cognitive dysfunction and cell death are unclear. Numerous therapeutic approaches that target the production, toxicity and removal of Ab are being developed worldwide. Although therapeutic treatment for AD may be imminent, the value and effectiveness of such treatment are largely dependent on early diagnosis of the disease. This review summarizes current knowledge of Ab clearance, transport and degradation, and evaluates the use of such information in the development of diagnostic tools. The conflicting results of plasma Ab ELISAs are discussed, as are the more promising results of Ab imaging by positron emission tomography. Current knowledge of Ab-binding proteins and Ab-degrading enzymes is analysed in the context of a potential therapy for AD. Transport across the blood-brain barrier by the receptor for advanced glycation end products and efflux via the multi-ligand lipoprotein receptor LRP-1 is also reviewed. Enhancing clearance and degradation of Ab remains an attractive therapeutic strategy, and improved understanding of Ab clearance may lead to advances in diagnostics and interventions designed to prevent or delay the onset of AD.

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Section: Introductionmentioning

confidence: 99%

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

et al. 2008

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“…This indicated that at least one other genetic locus for AD existed. As a result, 501 Rademakers et al: Genetics of Early-Onset Alzheimer Dementia TheScientificWorldJOURNAL (2003) 3, 497-519 genome-wide scans were initiated in several laboratories, leading to the identification of an AD locus on chromosome 14q24.3 [47,48,49,50] and the identification of mutations in the PSEN1 gene [51]. Only a few months later, PSEN2 (located on chromosome 1q42.3) was identified based on its homology to PSEN1 and genetic linkage to this chromosomal region in a series of German AD-families originating from the Volga valley in Russia [52,53].…”

Section: Identification Of the Psens: Gene And Protein Structurementioning

confidence: 99%

Genetics of Early-Onset Alzheimer Dementia

Rademakers

Cruts

Broeckhoven

2003

The Scientific World JOURNAL

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Alzheimer's dementia (AD) is the most common degenerative disorder of the central nervous system. Although the onset of dementia is above 65 years of age in the majority of the patients (late-onset AD, LOAD), a small subgroup of patients develops AD before 65 years of age (early-onset AD, EOAD). To date 3 genes responsible for EOAD have been identified: the amyloid precursor protein gene (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). PSEN1 is the most frequently mutated EOAD gene with a mutation frequency of 18 to 50% in autosomal dominant EOAD. In addition, the ε4 allele of the gene encoding apolipoprotein E (APOE) was identified as a risk factor for both LOAD and EOAD. Many studies reported other susceptibility genes, but the APOE 4 alelle has been the only risk factor that was consistently replicated in all AD populations. Extensive cell biology research in the past ten years led to the hypothesis that the 4 EOAD genes lead to AD through a common biological pathway resulting in abnormal APP processing by subtle different mechanisms. Now, transgenic mice are produced to study the influence of EOAD mutations in vivo, eventually leading to the development of novel therapeutic strategies. KEYWORDS:Alzheimer dementia, neurodegeneration, mutations, linkage analysis, association analysis, mouse models DOMAINS: genetics (man), aging, neuroscience INTRODUCTIONAlzheimer's disease (AD) is a degenerative disorder of the central nervous system that causes progressive memory loss and cognitive decline during mid to late adult life, leading to dementia and ultimately death. AD is the most common form of dementia in the elderly, and represents the fourth largest cause of death in the developed world. In the near future, the impact of AD on our society will dramatically increase since, as populations live longer, the number of elderly people continues to grow.The clinical symptoms of AD display a substantial overlap with clinical symptoms observed in other neurodegenerative disorders with dementia as accompanying feature, such as *Corresponding author. Address: Department of Molecular Genetics (VIB8), Neurogenetics Group, University of Antwerp (UIA), Universiteitsplein 1, B-2610 Antwerpen, Belgium; Tel: +32 3 8202601/Fax: +32 3 8202541 ©2003 with author.497 Rademakers et al.: Genetics of Early-Onset Alzheimer Dementia TheScientificWorldJOURNAL (2003) 3, 497-519 frontotemporal dementia (FTD) and Creutzfeldt Jacob's disease (CJD). Therefore a definite diagnosis of AD can only be obtained at autopsy. Extensive neuronal loss, and two particular brain lesions in the cerebral cortex, hippocampus, and amygdala characterize AD: the senile plaques (SPs) and neurofibrillary tangles (NFTs). The SPs are compact extracellular deposits that consist of a large amyloid β (Aβ) core surrounded by dystrophic neurites. NFTs are intraneuronal inclusions of paired helical filaments (PHF) that are mainly composed of hyperphosphorylated microtubule associated protein tau (MAPT).Based on the age at which the first clinical symptoms become...

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“…George-Hyslop et al, 1992;Van Broeckhoven et al, 1992; Levy-Lahad et al, 1995b). The products of these genes have been recently identified (Levy-Lahad et al, 1995a;Li et al, 1995;Rogaev et al, 1995;Sherrington et al, 1995) and named presenilin 1 and 2 (PSI and PS2), respectively.…”

mentioning

confidence: 99%

α‐Secretase‐Derived Product of β‐Amyloid Precursor Protein Is Decreased by Presenilin 1 Mutations Linked to Familial Alzheimer's Disease

Ancolio

Marambaud

Dauch

et al. 1997

Journal of Neurochemistry

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Recent reports indicate that missense mutations on presenilin (PS) 1 are likely responsible for the main early-onset familial forms of Alzheimer's disease (FAD). Consensual data obtained through distinct histopathological, cell biology, and molecular biology approaches have led to the conclusion that these PSi mutations clearly trigger an increased production of the 42-amino-acid-long species of /1-amyloid peptide (A/I). Here we show that overexpression of wild-type PSi in HK293 cells increases A/I40 secretion. By contrast, FAD-linked mutants of PSi trigger increased secretion of both A/340 and A/342 but clearly favor the production of the latter species. We also demonstrate that overexpression of the wild-type PSi augments the a-secretase-derived C-terminally truncated fragment of /3-amyloid precursor protein (APPc~)recovery, whereas transfectants expressing mutated PSi secrete drastically lower amounts of APPcr when compared with cells expressing wild-type PSi . This decrease was also observed when comparing double transfectants overexpressing wild-type /3-amyloid precursor protein and either PSi or its mutated congener Ml 46V-PS1. Altogether, our data indicate that PS mutations linked to FAD not only trigger an increased ratio of A/342 over total A/I secretion but concomitantly downregulate the production of APPa. Key Words: Familial Alzheimer's disease-Presenilin 1 -a-SecretaseAPPa-~3-Amyloidpeptide-/3-Amyloid precursor protein. J. Neurochem. 69, 2494Neurochem. 69, -2499Neurochem. 69, (1997.Several lines of genetic evidence have delineated two loci located on chromosomes 14 and 1 clearly associated with early-onset forms of familial Alzheimer's disease (FAD) (Mullan et al., 1992;Schellenberg et al., 1992;St. George-Hyslop et al., 1992;Van Broeckhoven et al., 1992; Levy-Lahad et al., 1995b). The products of these genes have been recently identified (Levy-Lahad et al., 1995a;Li et al., 1995;Rogaev et al., 1995;Sherrington et al., 1995) and named presenilin 1 and 2 (PSI and PS2), respectively. To date, >40 missense mutations (for review, see Van Broeckhoven, 1995;Haass, 1996; and one deletion (Perez-Tur et al., 1995) occurring on PSI likely responsible for most FAD have been identified, whereas only two take place on the PS2 sequence (Levy-Lahad et al., 1995b;Rogaev et al., 1995).The typical transmembrane structure of these two homologous proteins could suggest a receptor, channel, or more structural functions. We recently documented the lack of effect of PS1 and some of its FADlinked mutated analogues on Xenopus oocyte membrane currents (Dauch et al., 1997), ruling out the possible contribution or control of this protein in the regulation of ionic currents in Xenopus oocytes. Recent studies have suggested that, more likely, PSs occur as intermediates controlling the maturation and/or routing of /I-amyloid precursor protein (,8APP). First, the neuropathological characterization of the cortex of several cases with PSI mutations leads to the predominant detection of ,8-amyloid (A/I) peptide 42 (Lemer...

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Mapping of a gene predisposing to early–onset Alzheimer's disease to chromosome 14q24.3

Cited by 294 publications

References 26 publications

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

Genetics of Early-Onset Alzheimer Dementia

α‐Secretase‐Derived Product of β‐Amyloid Precursor Protein Is Decreased by Presenilin 1 Mutations Linked to Familial Alzheimer's Disease

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