Search

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 theVDRis 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. [ABSTRACT FROM AUTHOR]

In a mouse mutagenesis screen, we isolated a mutant. Myshkin (Myk), with autosomal dominant complex partial and secondarily generalized seizures, a greatly reduced threshold for hippocampal seizures in vitro. posttetanic hyperexcitability of the CA3-(A1 hippocampal pathway. and neuronal degeneration in the hippocampus. Positional cloning and functional analysis revealed that Myk/+ mice carry a mutation (1810N) which renders the normally expressed Na+,K+ATPase α3 isoform inactive. Total Na+,K+-ATPase activity was reduced by 42% in Myk/+ brain. The epilepsy in Myk/+ mice and in vitro hyperexcitability could be prevented by delivery of additional copies of wild-type Na+,K+-ATPase α3 by transgenesis. which also rescued Na+,K+-ATPase activity. Our findings reveal the functional significance of the Na+,K+-ATPase α3 isoform in the control of epileptiform activity and seizure behavior. [ABSTRACT FROM AUTHOR]

Focuses on the Β-Catenin and TCF mediate cell positioning in the intestinal epithelium. Definition of and stabilization of the pattern in the intestinal epithelium; Passive migration versus active repulsion; Accumulation of β-catenin in the intestinal epithelium.

Determines whether mice deficient in the ataxia telangiectasia mutated (ATM) gene were at increased risk for birth defects initiated by a model teratogen, ionizing radiation, that enhances formation of reactive oxygen species. Role of ATM as a teratologic suppressor; Process of cell death during embryonic development; Nature of neuronal cell death observed in ATM null mice.

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., (Copyright © 2014 the authors 0270-6474/14/347091-11$15.00/0.)