Depletion of adult neurogenesis exacerbates cognitive deficits in Alzheimer’s disease by compromising hippocampal inhibition

Molecular Neurodegeneration

Michael Hsu¹  Carolyn Hollands¹  Matthew Kyle Tobin¹  Orly Lazarov¹  Kianna Musaraca¹  Rachana Mishra¹  Steven G. Kernie²  Tzong-Shiue Yu² 

[1] Department of Anatomy and Cell Biology, College of Medicine, The University of Illinois at Chicago;Department of Pediatrics and Pathology & Cell Biology, Columbia University College of Physicians and Surgeons;

关键词: Alzheimer’s disease;    Hippocampal neurogenesis;    Learning and memory;    Hippocampal circuit;    Tau phosphorylation;   

DOI  :  10.1186/s13024-017-0207-7

来源: DOAJ

【 摘 要 】

Abstract Background The molecular mechanism underlying progressive memory loss in Alzheimer’s disease is poorly understood. Neurogenesis in the adult hippocampus is a dynamic process that continuously changes the dentate gyrus and is important for hippocampal plasticity, learning and memory. However, whether impairments in neurogenesis affect the hippocampal circuitry in a way that leads to memory deficits characteristic of Alzheimer’s disease is unknown. Controversial results in that regard were reported in transgenic mouse models of amyloidosis. Methods Here, we conditionally ablated adult neurogenesis in APPswe/PS1ΔE9 mice by crossing these with mice expressing nestin-driven thymidine kinase (δ-HSV-TK). Results These animals show impairment in performance in contextual conditioning and pattern separation tasks following depletion of neurogenesis. Importantly, these deficits were not observed in age-matched APPswe/PS1ΔE9 or δ-HSV-TK mice alone. Furthermore, we show that cognitive deficits were accompanied by the upregulation of hyperphosphorylated tau in the hippocampus and in immature neurons specifically. Interestingly, we observed upregulation of the immediate early gene Zif268 (Egr-1) in the dentate gyrus, CA1 and CA3 regions of the hippocampus following learning in the neurogenesis-depleted δ-HSV-TK mice. This may suggest overactivation of hippocampal neurons in these areas following depletion of neurogenesis. Conclusions These results imply that neurogenesis plays an important role in the regulation of inhibitory circuitry of the hippocampus. This study suggests that deficits in adult neurogenesis may contribute to cognitive impairments, tau hyperphosphorylation in new neurons and compromised hippocampal circuitry in Alzheimer’s disease.

【 授权许可】

Unknown