Alzheimer's disease (AD) represents an urgent yet unmet challenge for modern society, calling for exploration of innovative targets and therapeutic approaches. Astrocytes, main homeostatic cells in the CNS, represent promising cell-target. Our aim was to investigate if deletion of the regulatory CaNB1 subunit of calcineurin in astrocytes could mitigate AD-related memory deficits, neuropathology, and neuroinflammation. We have generated two, acute and chronic, AD mouse models with astrocytic CaNB1 ablation (ACN-KO). In the former, we evaluated the ability of β-amyloid oligomers (AβOs) to impair memory and activate glial cells once injected in the cerebral ventricle of conditional ACN-KO mice. Next, we generated a tamoxifen-inducible astrocyte-specific CaNB1 knock-out in 3xTg-AD mice (indACNKO-AD). CaNB1 was deleted, by tamoxifen injection, in 11.7-month-old 3xTg-AD mice for 4.4 months. Spatial memory was evaluated using the Barnes maze; β-amyloid plaques burden, neurofibrillary tangle deposition, reactive gliosis, and neuroinflammation were also assessed. The acute model showed that ICV injected AβOs in 2-month-old wild type mice impaired recognition memory and fostered a pro-inflammatory microglia phenotype, whereas in ACN-KO mice, AβOs were inactive. In indACNKO-AD mice, 4.4 months after CaNB1 depletion, we found preservation of spatial memory and cognitive flexibility, abolishment of amyloidosis, and reduction of neurofibrillary tangles, gliosis, and neuroinflammation. Our results suggest that ACN is crucial for the development of cognitive impairment, AD neuropathology, and neuroinflammation. Astrocyte-specific CaNB1 deletion is beneficial for both the abolishment of AβO-mediated detrimental effects and treatment of ongoing AD-related pathology, hence representing an intriguing target for AD therapy.

中文翻译：

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星形细胞钙调神经磷酸酶 B1 的基因缺失可预防急性和慢性阿尔茨海默病小鼠模型的认知障碍和神经病理学发展

阿尔茨海默病（AD）是现代社会面临的一个紧迫但尚未解决的挑战，需要探索创新的靶点和治疗方法。星形胶质细胞是中枢神经系统中的主要稳态细胞，是有前途的细胞靶标。我们的目的是研究星形胶质细胞中钙调神经磷酸酶调节性 CaNB1 亚基的缺失是否可以减轻 AD 相关的记忆缺陷、神经病理学和神经炎症。我们已经建立了两种急性和慢性 AD 小鼠模型，采用星形细胞 CaNB1 消融 (ACN-KO)。在前者中，我们评估了将 β-淀粉样蛋白寡聚物 (AβO) 注射到条件性 ACN-KO 小鼠脑室后损害记忆和激活神经胶质细胞的能力。接下来，我们在 3xTg-AD 小鼠 (indACNKO-AD) 中产生了他莫昔芬诱导的星形胶质细胞特异性 CaNB1 敲除。通过在 11.7 个月大的 3xTg-AD 小鼠中注射他莫昔芬，CaNB1 被删除了 4.4 个月。使用巴恩斯迷宫评估空间记忆；还评估了β-淀粉样斑块负荷、神经原纤维缠结沉积、反应性神经胶质增生和神经炎症。急性模型显示，ICV 在 2 个月大的野生型小鼠中注射 AβO 会损害识别记忆并培养促炎性小胶质细胞表型，而在 ACN-KO 小鼠中，AβO 不活跃。在 indACNKO-AD 小鼠中，CaNB1 耗尽后 4.4 个月，我们发现空间记忆和认知灵活性得以保留，淀粉样变性消失，神经原纤维缠结、神经胶质增生和神经炎症减少。我们的结果表明，ACN 对于认知障碍、AD 神经病理学和神经炎症的发展至关重要。星形胶质细胞特异性 CaNB1 缺失有利于消除 AβO 介导的有害影响和治疗持续的 AD 相关病理，因此代表了 AD 治疗的一个有趣的靶点。