BCI‐838, an orally active mGluR2/3 antagonist pro‐drug, mimics the beneficial effects of physical exercise on neurogenesis, behavior and exercise‐related molecular pathways in an Alzheimer’s disease mouse model

Modulation of physical exercise (PE) represents an intervention that may delay, slow, or prevent mild cognitive impairment (MCI) or dementia due to Alzheimer’s disease (AD). One mechanism proposed to underlie beneficial effects of PE involves the apparent stimulation of adult hippocampal neurogenesis (AHNG). BCI‐838 is a pro‐drug whose metabolite BCI‐632 is one of the most active proneurogenic agents known and is an antagonist at group II metabotropic receptors (mGluR2/3). The drug stimulates AHNG while enhancing learning behavior and exerting anxiolytic and antidepressant properties. We previously demonstrated that the administration of BCI‐838 to a mouse model of cerebral and cerebrovascular accumulation of oligomeric AbE22Q (APPE693Q = “Dutch”) reduced learning behavior impairment and anxiety, both of which are associated with the phenotype of Thy1.1‐Dutch APP mice (Kim et al., Mol Psych 2014). Herein, we sought to determine whether BCI‐838 might substitute for PE, and/or whether treatment with a BCI‐838+PE combination might demonstrate synergistic effects in a mouse model of amyloidosis (APPKM670/671NL/PSEN1Δexon9 = APP/PS1).