Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Geriatrics, Renmin Hospital of Wuhan University, Wuhan, China.
J Alzheimers Dis. 2018;66(4):1559-1576. doi: 10.3233/JAD-180782.
Chronic cerebral hypoperfusion (CCH) affects the aging population and especially patients with neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease. CCH is closely related to the cognitive dysfunction in these diseases. Glucagon-like peptide-2 receptor (GLP2R) mRNA and protein are highly expressed in the gut and in hippocampal neurons. This receptor is involved in the regulation of food intake and the control of energy balance and glucose homeostasis. The present study employed behavioral techniques, electrophysiology, western blotting, immunohistochemistry, quantitative real time polymerase chain reaction (qRT-PCR), and Golgi staining to investigate whether the expression of GLP2R changes after CCH and whether GLP2R is involved in cognitive impairment caused by CCH. Our findings show that CCH significantly decreased hippocampal GLP2R mRNA and protein levels. GLP2R upregulation could prevent CCH-induced cognitive impairment. It also improved the CCH-induced impairment of long-term potentiation and long-term depression. Additionally, GLP2R modulated after CCH the AKT-mTOR-p70S6K pathway in the hippocampus. Moreover, an upregulation of the GLP2R increased the neurogenesis in the dentate gyrus, neuronal activity, and density of dendritic spines and mushroom spines in hippocampal neurons. Our findings reveal the involvement of GLP2R via a modulation of the AKT-mTOR-p70S6K pathway in the mechanisms underlying CCH-induced impairments of spatial learning and memory. We suggest that the GLP2R and the AKT-mTOR-p70S6K pathway in the hippocampus are promising targets to treat cognition deficits in CCH.
慢性脑灌注不足（CCH）影响老年人群体，特别是患有神经退行性疾病（如阿尔茨海默病或帕金森病）的患者。CCH 与这些疾病中的认知功能障碍密切相关。胰高血糖素样肽-2 受体（GLP2R）mRNA 和蛋白在肠道和海马神经元中高度表达。该受体参与食物摄入的调节以及能量平衡和葡萄糖稳态的控制。本研究采用行为技术、电生理学、western blot、免疫组织化学、实时定量聚合酶链反应（qRT-PCR）和高尔基染色，来研究 CCH 后 GLP2R 的表达是否发生变化，以及 GLP2R 是否参与 CCH 引起的认知障碍。我们的研究结果表明，CCH 显著降低了海马 GLP2R mRNA 和蛋白水平。GLP2R 的上调可以预防 CCH 引起的认知障碍。它还改善了 CCH 引起的长时程增强和长时程抑制的损害。此外，GLP2R 调节 CCH 后海马中的 AKT-mTOR-p70S6K 通路。此外，GLP2R 的上调增加了齿状回的神经发生、神经元活性以及海马神经元树突棘和蘑菇状棘的密度。我们的研究结果揭示了 GLP2R 通过调节 AKT-mTOR-p70S6K 通路在 CCH 引起的空间学习和记忆损伤机制中的作用。我们建议，海马中的 GLP2R 和 AKT-mTOR-p70S6K 通路是治疗 CCH 认知缺陷的有前途的靶点。
