Evidence for genetic linkage of Alzheimer’s disease to chromosome 10q. Science

Harvard University, Cambridge, Massachusetts, United States
Science (Impact Factor: 33.61). 01/2001; 290(5500):2302-3. DOI: 10.1126/science.290.5500.2302
Source: PubMed


Recent studies suggest that insulin-degrading enzyme (IDE) in neurons and microglia degrades Abeta, the principal component of beta-amyloid and one of the neuropathological hallmarks of Alzheimer's disease (AD). We performed parametric and nonparametric linkage analyses of seven genetic markers on chromosome 10q, six of which map near the IDE gene, in 435 multiplex AD families. These analyses revealed significant evidence of linkage for adjacent markers (D10S1671, D10S583, D10S1710, and D10S566), which was most pronounced in late-onset families. Furthermore, we found evidence for allele-specific association between the putative disease locus and marker D10S583, which has recently been located within 195 kilobases of the IDE gene.

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Available from: Rudy Tanzi, Oct 14, 2015
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    • "It is worth noting that factors that attenuate Fas signaling have been suggested per se as a potential avenue for therapeutic intervention for AD [43] since increased levels of Fas protein have been reported in the brain and cerebrospinal fluid of AD patients [44], [45] and the Fas gene is located in the 10q24.1 region showing linkage to late onset AD [46], [47] with polymorphisms in Fas having shown association with AD progression [48], [49]. What would increase the chances of success of a combination of GSK-3 inhibitors and Fas signaling-blockers for AD. "
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    ABSTRACT: Glycogen synthase kinase-3 (GSK-3) inhibitors have been postulated as useful therapeutic tools for the treatment of chronic neurodegenerative and neuropsychiatric diseases. Nevertheless the clinical use of these inhibitors has been limited by their common side effects. Lithium, a non-selective GSK-3 inhibitor has been classically administered to treat bipolar patients but its prescription is decreasing due to its frequent side effects such as hand tremor. This toxicity seems to be higher in the elderly and a clinical trial with lithium for Alzheimer's disease was stopped due to high rate of discontinuation. We have previously described a mechanism for the adverse effects of chronic lithium that involves neuronal apoptosis via Fas signaling. As lithium inhibits many other enzymatic activities such as inositol monophosphatase and histone deacetylase, here we aim to genetically test whether GSK-3 inhibition induces those adverse effects through Fas receptor. For this purpose we took advantage of a transgenic mouse line with decreased GSK-3 activity (Tet/DN-GSK-3 mice) that shows increased rate of neuronal apoptosis as well as motor deficits and brought it to a Fas deficient background (lpr mice). We found that apoptosis induced by GSK-3 inhibition was absent in Fas deficient background. Interestingly, motor deficits were also absent in Fas deficient Tet/DN-GSK-3 mice. These results demonstrate that Fas signaling contributes to the neurological toxicity of GSK-3 inhibition and suggest that a combination of GSK-3 inhibitors with blockers of Fas signaling could help to improve the application of GSK-3 inhibitors to clinics.
    PLoS ONE 08/2013; 8(8):e70952. DOI:10.1371/journal.pone.0070952 · 3.23 Impact Factor
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    • "One of the functionally plausible candidate genes lying within the genetic region showing evidence for association or linkage reported by these studies is IDE occurring in a ~250kb haplotype block with KIFF11 and HHEX. Following the initial report on linkage and association of markers around IDE with LOAD (Bertram et al., 2000), some studies that used LOAD as the phenotype did not find an association (Cousin et al., 2009; Reiman et al., 2007) but other independent studies identified haplotypes spanning the IDE-KIFF-HHEX complex that show association with LOAD risk or intermediate LOAD phenotypes (Ertekin- Taner et al., 2004; Prince et al., 2003), including CSF tau levels, MMSE scores, senile plaque and neurofibrillary tangle density, and age-at-onset (Prince et al., 2003). The same haplotypes were associated with plasma Aβ levels in 24 extended Caucasian LOAD families, and with LOAD status in two independent case control series (Ertekin-Taner et al., 2004). "
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    ABSTRACT: Genetic linkage and association studies in late-onset Alzheimer's disease (LOAD) or its endophenotypes have pointed to several regions on chromosome 10q, among these the ∼ 250 kb linkage disequilibrium (LD) block harboring the genes IDE, KIF1, and HHEX. We explored the association between variants in the genomic region harboring the IDE-KIF11-HHEX complex with plasma Aβ40 and Aβ42 levels in a case-control cohort of Caribbean Hispanics. First, we performed single marker linear regression analysis relating the individual single nucleotide polymorphisms (SNPs) with plasma Aβ40 and Aβ42 levels. Then we performed 3-SNP sliding window haplotype analyses, correcting all analyses for multiple testing. Out of 32 SNPs in this region, 3 SNPs in IDE (rs2421943, rs12264682, rs11187060) were associated with plasma Aβ40 or Aβ42 levels in single marker and haplotype analyses after correction for multiple testing. All these SNPs lie within the same LD block, and are in LD with the previously reported haplotypes. Our findings provide support for an association in the IDE region on chromosome 10q with Aβ40 and 42 levels.
    Neurobiology of aging 01/2012; 33(1):199.e13-7. DOI:10.1016/j.neurobiolaging.2010.07.005 · 5.01 Impact Factor
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    • "The gene encoding IDE (IDE), located on chromosome 10q23.33, represents a strong AD candidate gene because of its location near a “suggestive” linkage peak (10q24) found in two genome-wide linkage studies of late-onset AD (LOAD) families [10], [11] and a “significant” linkage peak (10q) in a third [12]. Several studies have reported significant association of IDE haplotypes with LOAD [13], [14], [15], as well as with plasma Aβ42 levels in extended LOAD families [14], with plaque density [13] and cognitive function [14]. "
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    ABSTRACT: The insulin degrading enzyme (IDE) variant, v311 (rs6583817), is associated with increased post-mortem cerebellar IDE mRNA, decreased plasma β-amyloid (Aβ), decreased risk for Alzheimer's disease (AD) and increased reporter gene expression, suggesting that it is a functional variant driving increased IDE expression. To identify other functional IDE variants, we have tested v685, rs11187061 (associated with decreased cerebellar IDE mRNA) and variants on H6, the haplotype tagged by v311 (v10; rs4646958, v315; rs7895832, v687; rs17107734 and v154; rs4646957), for altered in vitro reporter gene expression. The reporter gene expression levels associated with the second most common haplotype (H2) successfully replicated the post-mortem findings in hepatocytoma (0.89 fold-change, p = 0.04) but not neuroblastoma cells. Successful in vitro replication was achieved for H6 in neuroblastoma cells when the sequence was cloned 5' to the promoter (1.18 fold-change, p = 0.006) and 3' to the reporter gene (1.29 fold change, p = 0.003), an effect contributed to by four variants (v10, v315, v154 and v311). Since IDE mediates Aβ degradation, variants that regulate IDE expression could represent good therapeutic targets for AD.
    PLoS ONE 06/2011; 6(6):e21429. DOI:10.1371/journal.pone.0021429 · 3.23 Impact Factor
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