A neuropathologic hallmark of Alzheimer's disease (AD) is the presence of senile plaques that contain neurotoxic amyloid-β protein (Aβ) species, which are generated by the cleavage of APP by secretases such as the γ-secretase complex, preferentially located in detergent-resistant membrane (DRM) regions and comprising endoproteolysed amino- and carboxyterminal fragments of presenilin, nicastrin, anterior pharynx defective 1, and presenilin enhancer 2.
γ-Secretase complex, the assembly of nicastrin (NCT), Presenilin (PS), Presenilin Enhancer-2 (PEN-2) and Anterior pharynx defective 1 (Aph-1), catalyzes the cleavage of amyloid precursor protein to generate amyloid-β protein (Aβ), the main culprit of Alzheimer's disease.
We demonstrate a reduction of membralin mRNA and protein levels in Alzheimer's disease (AD) brain, the latter of which inversely correlates with nicastrin abundance.
We found that the 5XFAD mice display higher expression of ApoE, ApoJ (clusterin), and nicastrin, three important proteins in AD that are known to participate in amyloid-β processing and clearance, as well as the neurological damage/glial marker protein GFAP and other proteins.
The senile plaques found in the brains of patients with Alzheimer's disease are mainly due to the accumulation of amyloid beta-peptides (A beta) that are liberated by gamma-secretase, a high molecular weight complex including presenilins, PEN-2, APH-1 and nicastrin.
Overall, our results indicate that the rs10752637 SNP can likely influence the expression of NCSTN, and that this may be an influencing factor during the pathogenesis of AD.
In conclusion, the expression of NCSTN-DeltaE16 transcript may confer some additional risk for developing Alzheimer disease beyond the risk due to ApoE-epsilon4 allele.
We also assessed genes for some proteins that constitute the gamma-secretase complex: nicastrin (NCSTN), presenilin enhancer-2 (PEN2), in addition to the AD risk factor apolipoprotein E (APOE).
In summary, this is the first report describing a novel skipped isoform of nicastrin which may suggest a new possible control mechanism based on the alternative splicing and nonsense-mediated mRNA decay to regulate brain protein expression and provide newer insights into potential implication in Alzheimer's disease.
Our investigation suggests that the two promoter SNPs are unrelated to the development of AD, however, further investigation at the promoter region of NCSTN may be necessary to address its potential implication of gene expression in AD.
Nicastrin was the first binding partner of presenilin (PS) shown to be a critical component of the presenilin/gamma-secretase complex essential in development and differentiation, and in generation of Alzheimer's disease Abeta amyloid peptide.
The gene encoding nicastrin, a major gamma-secretase component, modifies risk for familial early-onset Alzheimer disease in a Dutch population-based sample.
Nicastrin is a recently discovered protein interacting with presenilins and the beta-amyloid precursor protein, the proteins playing key roles in Alzheimer's disease and which, when mutated, appear responsible for early-onset familial forms of Alzheimer's disease.