Evidence supporting a role for the calcium‐sensing receptor in Alzheimer disease

Abstract

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 βamyloid could activate the calcium-sensing receptor. The receptor activation assays revealed that apoE as well as βamyloid 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.

The Calcium-Sensing Receptor as a Regulator of Cellular Fate in Normal and Pathological Conditions

“…Recent reports clearly point to a role for the CaSR as a regulator of early development and as a guardian of the homeostatic balance between proliferation and differentiation in adults [19,68,70,71,73,75,89,92]. The identification of CaSR mutations that cause FHH and hypocalcemia [93][94][95][96][97][98], and the recent discoveries implicating the dysregulation of CaSR signaling in many other diseases [99,[113][114][115][119][120][121][122][123][124], position the CaSR as a broad therapeutic target. Adverse side-effects will likely be a challenging issue in the putative use of CaSR-modulating agents for the treatment of such a broad range of tissuespecific diseases; therefore, future studies should focus on the development of CaSR-modulating drugs with a higher selectivity for the CaSR and specificity for the tissue of interest.…”

“…Indeed, Conley and colleagues identified a significant association between the length of a dinucleotide repeat within intron 4 (short versus long) of the CaSR and susceptibility to AD. It is noteworthy that this association was significant only for individuals without an APOE4 allele, a genotype considered to be an independent risk factor for the development of AD [113,114]. Furthermore, the authors provide evidence thatamyloid peptides and apoE protein activate CaSR signaling in cell culture, enhancing intracellular calcium levels and further promoting dysregulation of calcium homeostasis and calcium-dependent -amyloid aggregation.…”

The Intron 4 Polymorphism in the Calcium-Sensing Receptor Gene in Diabetes Mellitus and its Chronic Complications, Diabetic Nephropathy and Non-Diabetic Renal Disease

“…It has the effects on the secretion of parathyroid hormone-related peptide and impact on humoral hypercalcemia of malignancy [24]. There are a few documented cases of neurodegenerative disease linked to dysfunctional CaSR expression [25]. …”

CASR (Calcium-Sensing Receptor)

“…The CaSR is implicated to play a role in Alzheimer's disease (AD), with polymorphisms in intron 4 and exon 7 of the CaSR linked to AD status (Conley et al, 2009). Both amyloid-β peptide as well as apolipoprotein E protein can activate the CaSR with the former shown to have effects on calcium permeable, non-selective cation channels in hippocampal pyramidal neurons (Ye et al, 1997;Conley et al, 2009).…”

“…Both amyloid-β peptide as well as apolipoprotein E protein can activate the CaSR with the former shown to have effects on calcium permeable, non-selective cation channels in hippocampal pyramidal neurons (Ye et al, 1997;Conley et al, 2009). Nitrous oxide is responsible for the neuronal cell death characterizing late onset AD and the CaSR is necessary for the generation of a cofactor (tetrahydrobiopterin) important in the activation of nitrous oxide that is produced (in its inactive form) in response to amyloid-β peptidemediated stimulation of the receptor (Dal Pra et al, 2005;Chiarini et al, 2009).…”