Orally active mGluR2/3 metabotropic 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 activity represents an important intervention that may delay, slow, or prevent mild cognitive impairment (MCI) or dementia due to Alzheimer's disease (AD). One mechanism proposed to underlie the beneficial effect of physical exercise involves the apparent stimulation of adult hippocampal neurogenesis (AHN). BCI-838 is a pro-drug whose active metabolite BCI-632 is an antagonist at the group II metabotropic glutamate receptor (mGluR2/3). We previously demonstrated that administration of BCI-838 to a mouse model of cerebrovascular accumulation of oligomeric AβE693Q ( APPE693Q = "Dutch APP" ) reduced learning behavior impairment and anxiety, both of which are associated with the phenotype of the Dutch APP mice. Here we show that (i) administration of BCI-838, physical exercise, or a combination of BCI-838 and physical exercise enhanced AHN in a four-month old mouse model of AD amyloid pathology ( APPKM670/671NL/ PSEN1Δexon9 = APP/PS1), (ii) administration of BCI-838 alone or associated with physical exercise led to stimulation of AHN and improvement in both spatial and recognition memory, (iii) significantly, the hippocampal dentate gyrus transcriptome of APP/PS1 mice following BCI-838 treatment up-regulated brain-derived neurotrophic factor (BDNF), PIK3C2A of the PI3K-MTOR pathway, and metabotropic glutamate receptors, and down-regulated EIF5A of ketamine-modulating mTOR activity, and finally (iv) qPCR findings validate a significantly strong association between increased BDNF levels and BCI-838 treatment. Our study points to BCI-838 as a safe and orally active compound capable of mimicking the beneficial effect of exercise on AHN, learning behavior, and anxiety in a mouse model of AD neuropathology. ### Competing Interest Statement GP, MB, JBN, JVH, GMP, AO, MAG, RDG, YW, BR, GAE have no competing interests to declare. MS has served as a consultant for Bayer Schering Pharma, Bristol-Meyers Squibb, Elan Corporation, Genentech, Medivation, Medpace, Pfizer, Janssen, Takeda Pharmaceutical Company Limited, and United Biosource Corporation. She receives research support from the NIH. FHG was a founder and on the SAB for BCI but no longer serves as a consultant or has stock because BCI no longer exists as a company. He has received funding from NIA, HIH, and NIMH on projects related to adult neurogenesis but not related to this or related compounds. CB is a former employee of BrainCells. BrainCells provided drug and advice. JTD has served as a consultant for Janssen and is an equity holder in Thorne HealthTech. BSG is a consultant for Anthem AI and a scientific advisor and consultant for Prometheus Biosciences. He has received consulting fees from GLG Research and honoraria from Virtual EP Connect. MEE receives research support from the NIH, the XDP Foundation, and the Cure Alzheimer's Fund. SG has served as a consultant for Diagenic and the Pfizer-Janssen Alzheimer's Immunotherapy Alliance. He received research support from Warner-Lambert, Pfizer, Baxter Healthcare, Amicus and Avid. He served on the DSMB for an amyloid vaccine trial by Elan Pharmaceuticals. He receives research support from the VA, NIH, ADDF and the Cure Alzheimer's Fund. MEE and SG have received compensation for chart review in the areas of cognitive neurology and pediatric neurology, respectively.