Neuroscience Institute, Dale and Deborah Smith Center for Alzheimer's Research and Treatment, Departments of Neurology, Southern Illinois University School of Medicine, Springfield, IL, USA.
Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL, USA.
J Alzheimers Dis. 2024 Nov;102(2):491-505. doi: 10.3233/JAD-240795. Epub 2024 Nov 14.
It is well established that glutamatergic neurotransmission plays an essential role in learning and memory. Previous studies indicate that glutamate dynamics shift with Alzheimer's disease (AD) progression, contributing to negative cognitive outcomes.
In this study, we characterized hippocampal glutamatergic signaling with age and disease progression in a knock-in mouse model of AD (APP).
At 2-4 and 18+ months old, male and female APP, APP, and C57BL/6 mice underwent cognitive assessment using Morris water maze (MWM) and Novel Object Recognition (NOR). Then, basal and 70 mM KCl stimulus-evoked glutamate release was measured in the dentate gyrus (DG), CA3, and CA1 regions of the hippocampus using a glutamate-selective microelectrode in anesthetized mice.
Glutamate recordings support elevated stimulus-evoked glutamate release in the DG and CA3 of young APP male mice that declined with age compared to age-matched control mice. Young female APP mice exhibited increased glutamate clearance in the CA1 that slowed with age compared to age-matched control mice. Male and female APP mice exhibited decreased CA1 basal glutamate levels, while males also showed depletion in the CA3. Cognitive assessment demonstrated impaired spatial cognition in aged male and female APP mice, but only aged females displayed recognition memory deficits compared to age-matched control mice.
These findings confirm a sex-dependent hyper-to-hypoactivation glutamatergic paradigm in APP mice. Further, data illustrate a sexually dimorphic biological aging process resulting in a more severe cognitive phenotype for female APP mice than their male counterparts. Research outcomes mirror that of human AD pathology and provide further evidence of divergent AD pathogenesis between sexes.
谷氨酸能神经传递在学习和记忆中起着至关重要的作用，这一点已得到充分证实。先前的研究表明，谷氨酸动力学随着阿尔茨海默病（AD）的进展而发生变化，导致负面的认知结果。
在 AD（APP）的基因敲入小鼠模型中，本研究旨在研究年龄和疾病进展对海马谷氨酸能信号的影响。
在 2-4 个月和 18 个月以上时，雄性和雌性 APP、APP 和 C57BL/6 小鼠使用 Morris 水迷宫（MWM）和新物体识别（NOR）进行认知评估。然后，在麻醉小鼠中使用谷氨酸选择性微电极测量海马齿状回（DG）、CA3 和 CA1 区的基础和 70mM KCl 刺激诱发的谷氨酸释放。
谷氨酸记录支持年轻雄性 APP 小鼠 DG 和 CA3 中刺激诱发的谷氨酸释放增加，与同龄对照小鼠相比，随年龄增长而下降。年轻雌性 APP 小鼠在 CA1 中表现出谷氨酸清除率增加，与同龄对照小鼠相比，随年龄增长而减慢。雄性和雌性 APP 小鼠的 CA1 基础谷氨酸水平降低，而雄性小鼠 CA3 也出现耗竭。认知评估表明，年龄较大的雄性和雌性 APP 小鼠的空间认知受损，但只有年龄较大的雌性小鼠与同龄对照小鼠相比，出现识别记忆缺陷。
这些发现证实了 APP 小鼠中存在性别依赖性的谷氨酸能超激活到低激活范式。此外，数据表明存在性别二态的生物学衰老过程，导致雌性 APP 小鼠的认知表型比雄性小鼠更为严重。研究结果与人类 AD 病理学相吻合，并进一步证明了性别之间 AD 发病机制的差异。
