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Beneficial effects of physical exercise and an orally active mGluR2/3 antagonist pro-drug on neurogenesis and behavior in an Alzheimer’s amyloidosis model

ABSTRACT: BCI-838 is a pro-drug whose active metabolite BCI-632 is an antagonist at the group II metabotropic glutamate receptor (mGluR2/3). Hippocampal dentate gyrus of four-month old mouse model of AD amyloid pathology (APP/PS1) were investigated via transcriptomics analysis following BCI-838 treatment and physical exercise. Findings demonstrate 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. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE203554 | GEO | 2022/05/25

REPOSITORIES: GEO

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Project description:Mild exercise (ME) with an intensity below the lactate threshold (LT) is sufficient to enhance hippocampal function, while intense exercise (IE) above the LT negates such benefits. However, the question as to why ME more effectively enhances hippocampal function than does IE remains to be clarified. Here, we investigated adult hippocampal neurogenesis (AHN) as a mechanism of ME-induced cognitive improvement, and comprehensively delineated the transcriptomic profile of the hippocampus, using a rat whole-genome microarray approach through comparison with IE. Immunohistochemical results showed that less intense exercise (ME) is better suited to improve AHN, especially in regards to the survival and maturation of newborn neurons. DNA microarray analysis revealed that ME regulated more genes than did IE (ME: 604 genes, IE: 415 genes), and only 44 genes were modified with both exercise intensities. The identified molecular components did not comprise well-known factors related to exercise-induced AHN, such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF1), probably due to the timing of hippocampal tissue collection after the last training session and the technical feature of microarray. Rather, network analysis of the microarray data using Ingenuity Pathway Analysis algorithms revealed that the ME-influenced genes were principally related to lipid metabolism, protein synthesis and inflammatory response, which are recognized as associated with hippocampal neuroadaptations including AHN. In contrast, IE-influenced genes linked to immune response, a negative regulatory system of AHN and hippocampal function, were identified. Collectively, these results support our hypothesis that AHN could explain why ME enhances hippocampal function, and provide the ME-specific gene list that contain some potential regulators of this positive regulation. The list will become a foundation to elucidate the molecular pathway involving the ME-induced cognitive gain.

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Beneficial effects of physical exercise and an orally active mGluR2/3 antagonist pro-drug on neurogenesis and behavior in an Alzheimer’s amyloidosis model

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