Vitamin D receptor is present on the neuronal plasma membrane and is co-localized with amyloid precursor protein, ADAM10 or Nicastrin

Abstract

Our recent study indicated that vitamin D and its receptors are important parts of the amyloid processing pathway in neurons. Yet the role of vitamin D receptor (VDR) in amyloid pathogenesis is complex and all regulations over the production of amyloid beta cannot be explained solely with the transcriptional regulatory properties of VDR. Given that we hypothesized that VDR might exist on the neuronal plasma membrane in close proximity with amyloid precursor protein (APP) and secretase complexes. The present study primarily focused on the localization of VDR in neurons and its interaction with amyloid pathology-related proteins. The localization of VDR on neuronal membranes and its co-localization with target proteins were investigated with cell surface staining followed by immunofluorescence labelling. The FpClass was used for protein-protein interaction prediction. Our results demonstrated the localization of VDR on the neuronal plasma membrane and the co-localization of VDR and APP or ADAM10 or Nicastrin and limited co-localization of VDR and PS1. E-cadherin interaction with APP or the γ-secretase complex may involve NOTCH1, NUMB, or FHL2, according to FpClass. This suggested complex might also include VDR, which greatly contributes to Ca+2 hemostasis with its ligand vitamin D. Consequently, we suggested that VDR might be a member of this complex also with its own non-genomic action and that it can regulate the APP processing pathway in this way in neurons.

Paricalcitol accelerates BACE1 lysosomal degradation and inhibits calpain-1 dependent neuronal loss in APP/PS1 transgenic mice

“…In addition to BACE1, it has recently been demonstrated that VDRs are colocalized with APP and/or secretase complexes on the neuronal plasma membrane [32], and Aβ triggers neurodegeneration by dramatically suppressing VDR expression [33]. More importantly, vitamin D deficiency in early life affects neuronal differentiation, axonal connectivity, dopamine ontogeny and brain structure and function [34], but vitamin D supplementation protects neurons by preventing cytotoxicity and apoptosis and by upregulating VDR expression [7,33].…”

Serum vitamin D in patients with mild cognitive impairment and Alzheimer's disease

“…On the other hand, supplementation with vitamin D derivatives decreases the risk of AD (Dean, Bellgrove, & Hall, 2011). It has recently been found that vitamin D receptors are colocalized with amyloid precursor protein on the neuronal plasma membrane (Dursun & Gezen-Ak, 2017). Amyloid β (Aβ), the pathological hallmark of AD, degrades vitamin D receptor (Dursun, Gezen-Ak, & Yilmazer, 2010).…”

Diverse Effects of Combinations of Maternal-Neonatal VDR Polymorphisms and 25-Hydroxyvitamin D Concentrations on Neonatal Birth Anthropometry: Functional Phenocopy Variability Dependence, Highlights the Need for Targeted Maternal 25-Hydroxyvitamin D Cut-Offs during Pregnancy

“…Mechanistic pathways between VDR expression and offspring outcomes remain largely unclear. Apart from its classical intracellular pathways, which allows the ligand-bound VDR to form heterodimers with nuclear retinoid X receptor (RXR) and recruit co-factors to modulate gene transcription [ 31 ], vitamin D can also exert rapid non-genomic effects, probably via VDR located within the plasma membrane [ 32 , 33 ]. However, the functional effects of VDR and its allelic variants on birth anthropometry have not been elucidated, until recently.…”