Prodromal Glutamatergic Modulation with Riluzole Impacts Glucose Homeostasis and Spatial Cognition in Alzheimer's Disease Mice.
Prodromal Glutamatergic Modulation with Riluzole Impacts Glucose Homeostasis and Spatial Cognition in Alzheimer's Disease Mice.
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DOI：
10.3233/jad-221245
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发表时间：
2023
影响因子：
4
通讯作者：
Hascup, Erin R.
中科院分区：
文献类型：
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作者：
Findley, Caleigh A.;McFadden, Samuel A.;Cox, MaKayla F.;Sime, Lindsey N.;Peck, Mackenzie R.;Quinn, Kathleen;Bartke, Andrzej;Hascup, Kevin N.;Hascup, Erin R.
先前的研究支持阿尔茨海默病(AD)与代谢功能障碍之间的强烈联系，代谢功能障碍涉及葡萄糖、谷氨酸稳态和淀粉样蛋白病理之间的多方向相互作用。可溶性淀粉样蛋白-β(A-β)升高是AD相关认知功能下降的早期生物标志物，可导致人类和雄性转基因AD小鼠同时出现谷氨酸能和代谢紊乱。然而，目前尚不清楚对海马谷氨酸能活动的主要时间敏感靶向如何影响淀粉样变小鼠模型的血糖调节。以前的研究表明，使用神经保护性谷氨酸调节剂(利鲁唑)可以增加葡萄糖的摄取和代谢，支持葡萄糖和谷氨酸能动态平衡之间的联系。我们假设，通过利鲁唑治疗，靶向早期谷氨酸能高兴奋可以帮助减轻共存的代谢和淀粉样变性病理，目的是改善认知功能下降。我们对雄性和雌性转基因(AβPP/PS1)和敲入(APPNL)AD小鼠进行了早期干预研究，以评估前驱细胞谷氨酸能调节(2-6月龄)通过利鲁唑治疗对血糖稳态和空间认知的开关治疗效应。结果表明，利鲁唑干预后，随着疾病进展和治疗时间的延长，性别和基因型对血糖稳态和空间认知的特定影响。这些发现支持葡萄糖和谷氨酸能动态平衡与淀粉样蛋白病理的相互关联的本质，并呼吁进一步研究这种关系的靶向，以改善认知能力。
Prior research supports a strong link between Alzheimer’s disease (AD) and metabolic dysfunction that involves a multi-directional interaction between glucose, glutamatergic homeostasis, and amyloid pathology. Elevated soluble amyloid-β (Aβ) is an early biomarker for AD-associated cognitive decline that contributes to concurrent glutamatergic and metabolic dyshomeostasis in humans and male transgenic AD mice. Yet, it remains unclear how primary time-sensitive targeting of hippocampal glutamatergic activity may impact glucose regulation in an amyloidogenic mouse model. Previous studies have illustrated increased glucose uptake and metabolism using a neuroprotective glutamate modulator (riluzole), supporting the link between glucose and glutamatergic homeostasis. We hypothesized that targeting early glutamatergic hyperexcitation through riluzole treatment could aid in attenuating co-occurring metabolic and amyloidogenic pathologies with the intent of ameliorating cognitive decline. We conducted an early intervention study in male and female transgenic (AβPP/PS1) and knock-in (APPNL - F/NL - F) AD mice to assess the on- and off-treatment effects of prodromal glutamatergic modulation (2–6 months of age) on glucose homeostasis and spatial cognition through riluzole treatment. Results indicated a sex- and genotype-specific effect on glucose homeostasis and spatial cognition with riluzole intervention that evolved with disease progression and time since treatment. These findings support the interconnected nature of glucose and glutamatergic homeostasis with amyloid pathology and petition for further investigation into the targeting of this relationship to improve cognitive performance.