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Mol Psychiatry. 2014 Nov;19(11):1235-42. doi: 10.1038/mp.2014.87. Epub 2014 Aug 12.

Proneurogenic Group II mGluR antagonist improves learning and reduces anxiety in Alzheimer Aβ oligomer mouse.

Author information

1
Department of Neurology, Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
2
Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.
3
BrainCells, San Diego, CA, USA.
4
Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA.
5
1] Department of Neurology, Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA [2] Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
6
1] Department of Neurology, Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA [2] Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA [3] James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA.

Abstract

Proneurogenic compounds have recently shown promise in some mouse models of Alzheimer's pathology. Antagonists at Group II metabotropic glutamate receptors (Group II mGluR: mGlu2, mGlu3) are reported to stimulate neurogenesis. Agonists at those receptors trigger γ-secretase-inhibitor-sensitive biogenesis of Aβ42 peptides from isolated synaptic terminals, which is selectively suppressed by antagonist pretreatment. We have assessed the therapeutic potential of chronic pharmacological inhibition of Group II mGluR in Dutch APP (Alzheimer's amyloid precursor protein E693Q) transgenic mice that accumulate Dutch amyloid-β (Aβ) oligomers but never develop Aβ plaques. BCI-838 is a clinically well-tolerated, orally bioavailable, investigational prodrug that delivers to the brain BCI-632, the active Group II mGluR antagonist metabolite. Dutch Aβ-oligomer-forming APP transgenic mice (APP E693Q) were dosed with BCI-838 for 3 months. Chronic treatment with BCI-838 was associated with reversal of transgene-related amnestic behavior, reduction in anxiety, reduction in levels of brain Aβ monomers and oligomers, and stimulation of hippocampal neurogenesis. Group II mGluR inhibition may offer a unique package of relevant properties as an Alzheimer's disease therapeutic or prophylactic by providing both attenuation of neuropathology and stimulation of repair.

PMID:
25113378
PMCID:
PMC4217144
DOI:
10.1038/mp.2014.87
[Indexed for MEDLINE]
Free PMC Article

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