Association between variants in IDE-KIF11-HHEX and plasma amyloid β levels

Reitz, Christiane; Cheng, Rong; Schupf, Nicole; Lee, Joseph H.; Mehta, Pankaj; Rogaeva, Ekaterina; George-Hyslop, Peter St; Mayeux, Richard

doi:10.1016/j.neurobiolaging.2010.07.005

Cited by 21 publications

(14 citation statements)

References 13 publications

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“…Aβ inhibition of Eg5/kinesin 5 may also explain several previous observations that localization and function of various neurotransmitter receptors and other membrane proteins, including the NMDA receptor and the APP and PS proteins themselves, are disrupted in AD (Li et al, 1997; Honda et al, 2000; Almeida et al 2005; Snyder et al, 2005; Shah et al, 2009; Liu et al, 2010). The fact that some polymorphisms linked to KIF11/Eg5 are associated with increased AD risk and/or Aβ production (Feuk et al, 2005; Reitz et al, 2012) further strengthens this hypothesis.…”

Section: Discussionmentioning

confidence: 70%

Alzheimer amyloid beta inhibition of Eg5/kinesin 5 reduces neurotrophin and/or transmitter receptor function

Ari¹,

Borysov²,

Wu³

et al. 2014

Neurobiology of Aging

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The mechanism by which Aβ causes neuronal dysfunction/death in Alzheimer’s disease is unclear. Previously, we showed that Aβ inhibits several microtubule-dependent kinesin motors essential for mitosis and also present in mature neurons. Here we show that inhibition of kinesin 5 (Eg5) by Aβ blocks neuronal function by reducing transport of neurotrophin and neurotransmitter receptors to the cell surface. Specifically, cell-surface NGF/NTR(p75) and NMDA receptors decline in cells treated with Aβ or the Kin5 inhibitor monastrol, or expressing APP. Aβ and monastrol also inhibit NGF-dependent neurite outgrowth from PC12 cells and glutamate-dependent Ca++ entry into primary neurons. Like Aβ, monastrol inhibits long-term potentiation, a cellular model of NMDA-dependent learning and memory, and Kin5 activity is absent from APP/PS transgenic mice brain or neurons treated with Aβ. These data imply that cognitive deficits in AD may derive in part from inhibition of neuronal Eg5 by Aβ, resulting in impaired neuronal function/survival through receptor mis-localization. Preventing inhibition of Eg5 or other motors by Aβ may represent a novel approach to Alzheimer’s disease therapy.

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Section: Discussionmentioning

confidence: 70%

Alzheimer amyloid beta inhibition of Eg5/kinesin 5 reduces neurotrophin and/or transmitter receptor function

Ari¹,

Borysov²,

Wu³

et al. 2014

Neurobiology of Aging

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“…54–57 Another group reported an haplotypic association spanning the MMP3 gene. 58 Using the same SNPs, we did not replicate theses findings in our study (Supplementary Table 8).…”

Section: Discussionmentioning

confidence: 99%

A genome-wide association meta-analysis of plasma Aβ peptides concentrations in the elderly

et al. 2014

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Amyloid beta (Aβ) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aβ peptides’ functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma Aβ peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aβ-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aβ1–40 and Aβ1–42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P<1 × 10−5). Enrichment-pathway analyses revealed canonical pathways mainly involved in neuronal functions, for example, axonal guidance signaling. We also assessed the biological impact of the gene most strongly associated with plasma Aβ1–42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aβ1–42 secretion. In conclusion, our study results suggest that plasma Aβ peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of APP and its metabolites.

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“…Lower IDE expression has also been found to correlate with higher levels of cellular Aβ42 associated with PS1 mutations in cellular models. Several have found an association between a variant on IDE and plasma Aβ42 or Aβ40 levels (Carrasquillo, et al, 2010, Reitz, et al, 2012). However, data on the relation of the IDE locus with AD is conflicting.…”

Section: Discussionmentioning

confidence: 99%

Candidate genes for Alzheimer's disease are associated with individual differences in plasma levels of beta amyloid peptides in adults with Down syndrome

Schupf

Lee

Park

et al. 2015

Neurobiology of Aging

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We examined the contribution of candidate genes for Alzheimer’s disease (AD) on Chromosome 21 and other chromosomes to differences in Aβ peptide levels in a cohort of adults with DS, a population at high risk for AD. Participants were 254 non-demented adults with Down syndrome, 30–78 years of age. Genomic DNA was genotyped using an Illumina GoldenGate custom array. We used linear regression to examine differences in levels of Aβ peptides associated with the number of risk alleles, adjusting for age, sex, level of intellectual disability, race/ethnicity and the presence of the APOE ε4 allele. For Aβ42 levels, the strongest gene-wise association was found for a SNP on CAHLM1; for Aβ40 levels the strongest gene-wise associations were found for SNPs in IDE and SOD1, while the strongest gene-wise associations with levels of the Aβ42/Aβ40 ratio were found for SNPs in SORCS1. Broadly classified, variants in these genes may influence APP processing (CALHM1, IDE), vesicular trafficking (SORCS1), and response to oxidative stress (SOD1).

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Association between variants in IDE-KIF11-HHEX and plasma amyloid β levels

Cited by 21 publications

References 13 publications

Alzheimer amyloid beta inhibition of Eg5/kinesin 5 reduces neurotrophin and/or transmitter receptor function

Alzheimer amyloid beta inhibition of Eg5/kinesin 5 reduces neurotrophin and/or transmitter receptor function

A genome-wide association meta-analysis of plasma Aβ peptides concentrations in the elderly

Candidate genes for Alzheimer's disease are associated with individual differences in plasma levels of beta amyloid peptides in adults with Down syndrome

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