Genetic evidence for a novel familial Alzheimer's disease locus on chromosome 14

George-Hyslop, Peter St; Haines, Jonathan L.; Rogaev, Evgeny I.; Mortilla, M.; Vaula, Giovanna; Pericak‐Vance, M. A.; Foncin, J. F.; Montesi, M. P.; Bruni, Amalia C.; Sorbi, Sandro; Rainero, Innocenzo; Pinessi, Lorenzo; Pollen, Daniel A.; Polinsky, Ronald J.; Nee, Linda E.; Kennedy, James L.; Macciardi, Fabìo; Rogaeva, Ekaterina; Liang, Yan; Alexandrova, N.; Lukiw, Walter J.; Schlumpf, Karen S.; Tanzi, Rudolph E.; Tsuda, Takuya; Farrer, Lindsay A.; Cantú, J. M.; Duara, Ranjan; Amaducci, L.; Bergamini, L; Gusella, James F.; Roses, Allen D.; McLachlan, D. Crapper

doi:10.1038/ng1292-330

Cited by 415 publications

(96 citation statements)

References 24 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].…”

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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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“…Genetic linkage studies led to the mapping of a locus to chromosome 14q24.3, which appeared to account for almost 70% of all EOFAD cases (Schellenberg et al, 1992;St George-Hyslop et al, 1992;Van Broeckhoven et al, 1992). A novel gene named presenilin-1 (PSEN1) was identified in this region, whose product resembles an integral membrane protein with multiple transmembrane domains and five missense mutations were identified in this gene that co-segregates with EOFAD (Sherrington et al, 1995).…”

Section: Alzheimer's Diseasementioning

confidence: 99%

“…However, neither APP nor PSEN1 mutations appeared to be the genetic cause of EOFAD in certain other families including the Volga-German AD families, a group of related families suffering from EOFAD that descended from one German family (Schellenberg et al, 1992;St George-Hyslop et al, 1992). A genome-wide search in these EOFAD families helped identify a locus on chromosome 1q42 whose product showed amino acid sequence homology to PSEN1 and was accordingly named presenilin-2 (PSEN2) (Levy-Lahad et al, 1995).…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Role of Presenilin in Mitochondrial Oxidative Stress and Neurodegeneration in <em>Caenorhabditis elegans</em>

Sarasija¹,

Norman²

2018

Preprint

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Neurodegenerative diseases like Alzheimer's disease (AD) are poised to become a global health crisis, and therefore understanding the mechanisms underlying the pathogenesis is critical for the development of therapeutic strategies. Mutations in genes encoding presenilin occur in most familial Alzheimer's disease but the role of PSEN in AD is not fully understood. In this review, the potential modes of pathogenesis of AD are discussed, focusing on calcium homeostasis and mitochondrial function. Moreover, research using Caenorhabditis elegans to explore the effects of calcium dysregulation due to presenilin mutations on mitochondrial function, oxidative stress and neurodegeneration is explored.

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Genetic evidence for a novel familial Alzheimer's disease locus on chromosome 14

Cited by 415 publications

References 24 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

Role of Presenilin in Mitochondrial Oxidative Stress and Neurodegeneration in <em>Caenorhabditis elegans</em>

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