The Solomon Snyder Department of Neuroscience, The Johns Hopkins School of Medicine, PCTB 1004, 725 N. Wolfe Street, Baltimore, MD, 21205, USA.
Department of Pathology, The Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Avenue, Baltimore, MD, 21205, USA.
Behav Brain Funct. 2024 Apr 4;20(1):7. doi: 10.1186/s12993-024-00234-1.
Alzheimer's disease (AD) and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) are debilitating neurodegenerative diseases for which there are currently no cures. Familial cases with known genetic causes make up less than 10% of these diseases, and little is known about the underlying mechanisms that contribute to sporadic disease. Accordingly, it is important to expand investigations into possible pathways that may contribute to disease pathophysiology. Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) is a membrane-bound enzyme that acts at the cell surface to cleave the glycosylphosphatidylinositol (GPI)-anchor that tethers distinct proteins to the membrane. GDE2 abnormally accumulates in intracellular compartments in the brain of patients with AD, ALS, and ALS/FTD, indicative of GDE2 dysfunction. Mice lacking GDE2 (Gde2KO) show neurodegenerative changes such as neuronal loss, reduced synaptic proteins and synapse loss, and increased Aβ deposition, raising the possibility that GDE2 disruption in disease might contribute to disease pathophysiology. However, the effect of GDE2 loss on behavioral function and learning/memory has not been characterized.
Here, we show that GDE2 is expressed throughout the adult mouse brain in areas including the cortex, hippocampus, habenula, thalamus, and amygdala. Gde2KO and WT mice were tested in a set of behavioral tasks between 7 and 16 months of age. Compared to WT, Gde2KO mice display moderate hyperactivity that becomes more pronounced with age across a variety of behavioral tests assessing novelty-induced exploratory activity. Additionally, Gde2KO mice show reduced startle response, with females showing additional defects in prepulse inhibition. No changes in anxiety-associated behaviors were found, but Gde2KOs show reduced sociability. Notably, aged Gde2KO mice demonstrate impaired short/long-term spatial memory and cued fear memory/secondary contextual fear acquisition.
Taken together, these observations suggest that loss of GDE2 leads to behavioral deficits, some of which are seen in neurodegenerative disease models, implying that loss of GDE2 may be an important contributor to phenotypes associated with neurodegeneration.
阿尔茨海默病（AD）和肌萎缩侧索硬化症/额颞叶痴呆（ALS/FTD）是使人衰弱的神经退行性疾病，目前尚无治愈方法。具有已知遗传原因的家族病例占这些疾病的不到 10%，对于导致散发性疾病的潜在机制知之甚少。因此，扩大对可能导致疾病病理生理学的潜在途径的研究非常重要。甘油磷酸二酯磷酸二酯酶 2（GDE2 或 GDPD5）是一种膜结合酶，在细胞表面起作用，裂解将不同蛋白质固定在膜上的糖基磷脂酰肌醇（GPI）锚。AD、ALS 和 ALS/FTD 患者的大脑中 GDE2 异常积累在细胞内隔室中，表明 GDE2 功能障碍。缺乏 GDE2 的小鼠（Gde2KO）表现出神经退行性变化，如神经元丢失、突触蛋白和突触丢失减少以及 Aβ 沉积增加，这表明疾病中 GDE2 破坏可能导致疾病病理生理学。然而，尚未表征 GDE2 缺失对行为功能和学习/记忆的影响。
在这里，我们表明 GDE2 在成年小鼠大脑的各个区域表达，包括皮质、海马体、缰核、丘脑和杏仁核。在 7 至 16 个月大时，用一系列行为任务对 Gde2KO 和 WT 小鼠进行测试。与 WT 相比，Gde2KO 小鼠表现出中度多动，随着年龄的增长，在各种评估新奇诱导的探索性活动的行为测试中表现得更为明显。此外，Gde2KO 小鼠的惊跳反应减弱，雌性表现出额外的前脉冲抑制缺陷。未发现焦虑相关行为的变化，但 Gde2KOs 表现出社交能力下降。值得注意的是，年老的 Gde2KO 小鼠表现出短期/长期空间记忆和条件恐惧记忆/次要情景恐惧获得受损。
综上所述，这些观察结果表明，GDE2 的缺失导致行为缺陷，其中一些在神经退行性疾病模型中可见，这表明 GDE2 的缺失可能是与神经退行性相关表型的重要贡献者。
