Dual role of Aβ42Os in adult hippocampal neurogenesis regulated by mGluR5 at different stages of Alzheimer's disease

Abstract

Abstract Background Alzheimer's disease (AD) is a neurodegenerative disease leading to irreversible loss of neurons in the cerebral cortex and hippocampus. Adult hippocampal neurogenesis (AHN) drops sharply correlated with cognitive status in AD patients. Beta-amyloid (Aβ), involved in the pathogenesis of AD, has been shown to positively or negatively affect the generation of new neurons. Metabotropic glutamate receptor 5 (mGluR5) is present in neural stem cells (NSCs) and promotes neuronal proliferation. In the pathophysiology of AD, mGluR5 is a co-receptor of Aβ oligomers that bind to cellular prion proteins. However, the role of mGluR5 in adult hippocampal neurogenesis during AD progression remains unclear. Methods In this study, we verified the effects of different concentrations of Aβ42 on hippocampus neurogenesis in vivo and in vitro. To explore the role of mGluR5 in adult hippocampal neurogenesis of AD, mGluR5 was knocked down in 5XFAD mice and primary neural stem cells. Immunofluorescence, Western blotting, and Ca2+ measurement were used to verify the mechanism of mGluR5 in neurogenesis. Finally, the impact of mGluR5 on AD cognitive function was detected through Morris water maze, novel object recognition, passive avoidance test. Results AHN increased in the early stage and decreased in the late stage of 5XFAD mice. Picomolar concentrations of Aβ42Os promoted NSCs proliferation, nanomolar concentrations of Aβ42Os restrained NSCs proliferation and induced apoptosis. Knockdown of mGluR5 ameliorated the inhibitory effect of nanomolar concentrations of Aβ42Os on NSCs proliferation, promoted neuronal differentiation and maturation. The CaMK-II-Erk/CREB signaling pathway may be the key for mGluR5 to regulate neurogenesis. mGluR5 knockdown reversed cognitive deficits in 5XFAD mice. Conclusions The data presented demonstrate that mGluR5 is a modulator in the bidirectional regulation of Aβ42 on neurogenesis. Targeting mGluR5 ameliorates reduced adult hippocampal neurogenesis and cognitive dysfunction in the late stage of 5XFAD mice.