Evidence supporting a role for the calcium-sensing receptor in Alzheimer disease.
The calcium-sensing receptor (CASR) is a G-protein coupled, transmembrane receptor that responds to changes in Ca(2+) levels. We hypothesized that the CASR could have a role in Alzheimer disease (AD) given expression of the CASR in brain, knowledge that calcium dysregulation promotes susceptibility to neuronal cell damage, the important role that the CASR plays in calcium regulation, and the fact that systemic calcium homeostasis and G-protein signal transduction are altered in AD patients. To investigate the association of CASR variation in AD susceptibility, we genotyped a polymorphic dinucleotide repeat marker within intron 4, one SNP within the promoter region and three non-synonymous SNPs within exon 7 of the CASR gene and tested for association analysis, using a well-characterized cohort of AD cases (n = 692) and controls (n = 435). The dinucleotide repeat polymorphism was significantly associated with AD status (OR = 1.62; 95% CI: 1.27-2.07, P = 0.00037, Bonferroni corrected P = 0.0011) and the three non-synonymous SNP haplotype was boarderline associated with AD status (P = 0.032, Bonferroni corrected P = 0.096). Stratifying by APOE4 allele carrier status revealed that the significant association was only in non-APOE4 carriers (OR of 1.90; 95% CI: 1.37-2.62, P = 0.0001). We also investigated whether apoE or beta amyloid could activate the calcium-sensing receptor. The receptor activation assays revealed that apoE as well as beta amyloid activated the CASR and that the level of activation appeared to be isoform dependent for apoE. These data support our hypothesis that the CASR has a role in AD susceptibility, particularly in individuals without an APOE4 allele.
Conley
Yvette P
YP
Department of Health Promotion and Development, University of Pittsburgh, Pennsylvania, USA. yconley@pitt.edu
Mukherjee
Ankur
A
Kammerer
Candace
C
DeKosky
Steven T
ST
Kamboh
M Ilyas
MI
Finegold
David N
DN
Ferrell
Robert E
RE
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics; D019556:COS Cells; D016022:Case-Control Studies; D002522:Chlorocebus aethiops; D015331:Cohort Studies; D018900:Dinucleotide Repeats / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D044169:Receptors, Calcium-Sensing / Q000235:genetics / Q000502:physiology*
D053327:Apolipoprotein E4; D044169:Receptors, Calcium-Sensing