Search

Background:Alzheimer’s disease (AD) is characterized by cerebral deposition of amyloid-s (As), a series of peptides derived from the processing of the amyloid-s precursor protein (APP). To identify new genes potentially involved in AD pathogenesis, we recently performed a transcriptome analysis to screen for genes preferentially expressed in the hippocampus and located in chromosomal linkage regions for AD. This tissue expression profiling strategy identified CALHM1 (calcium homeostasis modulator 1) (Dreses-Werringloer et al., Cell. 2008, 133:1149-61). Here, we focused our attention on another candidate, growth arrest-specific 1 (Gas1), a gene coding for a glycosyl phosphatidylinositol (GPI)-anchored protein involved in central nervous system development. Methods: Using the HapMap database and data available from the recently published genome-wide association studies (GWAS; Lambert et al., Nat. Genet. 2009, 41:1094-1099; Harold et al., Nat. Genet. 2009, 41:1088-1093), we tested whether Gas1 single nucleotide polymorphisms could be associated with the risk of developing the disease. We then used immunocytochemistry, biochemical, and molecular biology approaches to determine whether Gas1 might functionally or physically interact with APP and whether Gas1 modulates APP metabolism. Results: No association between Gas1 and the risk of developing AD was found from the analysis of the publically available GWAS. However, immunofluorescence staining and co-immunoprecipitation analyses revealed that Gas1 can form a complex with APP in cells overexpressing Gas1 and APP, and also in primary neuronal cultures expressing endogenously Gas1 and APP. Gas1 expression was found to inhibit APP full glycosylation and to negatively control APP processing. Consequently, Gas1 overexpression led to a reduction of As production and conversely, Gas1 silencing increased As levels. Moreover, Gas1 expression inhibited APP trafficking to the cell surface by leading to a trafficking blockade of APP between the endoplasmic reticulum and the Golgi. Gas1 expression also resulted in a robust inhibition of APP transport into multivesicular bodies, further demonstrating that Gas1 negatively regulated APP intracellular trafficking.Conclusions:We report for the first time that Gas1 forms a complex with APP and controls APP maturation, trafficking, and processing to modulate As production. These results not only shed light on new mechanisms of APP maturation but also increase our understanding of Gas1 function.

A recent paper reported that a variant (rs2986017) of the calcium homeostasis modulator 1 (CALHM1) gene affects risk for late-onset Alzheimer's disease (AD). This study aims to investigate whether single nucleotide polymorphisms (SNPs) of the CALHM1 gene are associated with AD. SNPs in the genes of two other CALHM subtypes, CALHM2 and CALHM3, were also studied. Our study failed to detect any association between the SNPs of the three genes and AD. Although rs729211 showed marginal association in the APOE4 negative group, the linkage disequilibrium analysis results suggest this to be a false positive.

cerebrospinal fluid (CSF) series. Association analyses were performed using ANCOVA after adjustment for covariates. Power analyses were performed using PROC POWER in SAS. Results: We failed to detect association between CSF Ab42 levels and SNPs in SORL1 despite substantial statistical power to detect association. While we also failed to detect association between variants in GAB2 and CSF tau levels power to detect this association was limited. Finally, our data suggest that the minor allele of rs2986017, in CALHM1, is significantly associated with CSF Ab42 levels (p 1⁄4 0.0095). Conclusions: This association is consistent with previous reports suggesting that this non-synonymous coding substitution results in increased Ab levels in vitro and provides support for an Ab-related mechanism for modulating risk for AD. This finding provides further evidence that the use of CSF endophenotypes for genetic studies of AD can be an effective tool for understanding the biological mechanisms by which variants influence risk for LOAD.