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J Neurosci. 2014 May 21;34(21):7091-101. doi: 10.1523/JNEUROSCI.2711-13.2014.

1α,25-Dihydroxyvitamin D3 reduces cerebral amyloid-β accumulation and improves cognition in mouse models of Alzheimer's disease.

Author information

1
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, Toronto, Ontario, Canada, M5S 3M2.
2
Tanz Centre for Research in Neurodegenerative Diseases, Krembil Discovery Tower, Toronto, Ontario, Canada, M5T 2S8.
3
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada, M5S 3H2, and Tanz Centre for Research in Neurodegenerative Diseases, Krembil Discovery Tower, Toronto, Ontario, Canada, M5T 2S8.
4
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, Toronto, Ontario, Canada, M5S 3M2, ks.pang@utoronto.ca.

Abstract

We demonstrate a role of the vitamin D receptor (VDR) in reducing cerebral soluble and insoluble amyloid-β (Aβ) peptides. Short-term treatment of two human amyloid precursor protein-expressing models, Tg2576 and TgCRND8 mice, with 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], the endogenous active ligand of VDR, resulted in higher brain P-glycoprotein (P-gp) and lower soluble Aβ levels, effects negated with coadministration of elacridar, a P-gp inhibitor. Long-term treatment of TgCRND8 mice with 1,25(OH)2D3 during the period of plaque formation reduced soluble and insoluble plaque-associated Aβ, particularly in the hippocampus in which the VDR is abundant and P-gp induction is greatest after 1,25(OH)2D3 treatment, and this led to improved conditioned fear memory. In mice fed a vitamin D-deficient diet, lower cerebral P-gp expression was observed, but levels were restored on replenishment with VDR ligands. The composite data suggest that the VDR is an important therapeutic target in the prevention and treatment of Alzheimer's disease.

KEYWORDS:

Alzheimer's; P-glycoprotein; amyloid beta; blood-brain barrier; vitamin D receptor

PMID:
24849345
DOI:
10.1523/JNEUROSCI.2711-13.2014
[Indexed for MEDLINE]
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