1α,25-Dihydroxyvitamin D3 reduces cerebral amyloid-β accumulation and improves cognition in mouse models of Alzheimer's disease.
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.
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, Toronto, Ontario, Canada, M5S 3M2.
Matthew R
MR
Durk
Tanz Centre for Research in Neurodegenerative Diseases, Krembil Discovery Tower, Toronto, Ontario, Canada, M5T 2S8.
Kyung
K
Han
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, Toronto, Ontario, Canada, M5S 3M2.
Edwin C Y
EC
Chow
Tanz Centre for Research in Neurodegenerative Diseases, Krembil Discovery Tower, Toronto, Ontario, Canada, M5T 2S8.
Rosemary
R
Ahrens
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, Toronto, Ontario, Canada, M5S 3M2.
Jeffrey T
JT
Henderson
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.
Paul E
PE
Fraser
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, Toronto, Ontario, Canada, M5S 3M2, ks.pang@utoronto.ca.
K Sandy
KS
Pang
D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology*; D003213:Conditioning, Psychological / Q000187:drug effects; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D014815:Vitamins / Q000627:therapeutic use*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D014815:Vitamins; C118756:dihydroxy-vitamin D3; D014807:Vitamin D
Alzheimer's; P-glycoprotein; amyloid beta; blood-brain barrier; vitamin D receptor