Food restriction has been widely associated with beneficial effects on brain aging and age-related neurodegenerative diseases such as Alzheimer's disease. However, previous studies on the effects of food restriction on aging- or pathology-related cognitive decline are controversial, emphasizing the importance of the type, onset and duration of food restriction. In the present study, we assessed the effects of preventive every-other-day (EOD) feeding regimen on neurodegenerative phenotype in 5XFAD transgenic mice, a commonly used mouse model of Alzheimer's disease. EOD feeding regimen was introduced to transgenic female mice at the age of 2 months and the effects on amyloid-β (Aβ) accumulation, gliosis, synaptic plasticity, and blood-brain barrier breakdown were analyzed in cortical tissue of 6-month-old animals. Surprisingly, significant increase of inflammation in the cortex of 5XFAD fed EOD mice was observed, reflected by the expression of microglial and astrocytic markers. This increase in reactivity and/or proliferation of glial cells was accompanied by an increase in proinflammatory cytokine TNF-α, p38 MAPK and EAAT2, and a decrease in GAD67. NMDA receptor subunit 2B, related to glutamate excitotoxicity, was increased in the cortex of 5XFAD-EOD mice indicating additional alterations in glutamatergic signaling. Furthermore, 4 months of EOD feeding regimen had led to synaptic plasticity proteins reduction and neuronal injury in 5XFAD mice. However, EOD feeding regimen did not affect Aβ load and blood-brain barrier permeability in the cortex of 5XFAD mice. Our results demonstrate that EOD feeding regimen exacerbates Alzheimer's disease-like neurodegenerative and neuroinflammatory changes irrespective of Aβ pathology in 5XFAD mice, suggesting that caution should be paid when using food restrictions in the prodromal phase of this neurodegenerative disease.

中文翻译：

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每隔一天进食会加剧阿尔茨海默氏病5XFAD小鼠模型的炎症和神经元缺陷。

食物限制已与对脑衰老和与年龄有关的神经退行性疾病（如阿尔茨海默氏病）的有益作用广泛相关。但是，先前有关食物限制对衰老或病理相关的认知能力下降影响的研究存在争议，强调了食物限制的类型，发作和持续时间的重要性。在本研究中，我们评估了预防性隔日（EOD）喂养方案对5XFAD转基因小鼠（一种常见的阿尔茨海默氏病小鼠模型）的神经变性表型的影响。将EOD喂养方案引入2个月大的转基因雌性小鼠中，并分析了6个月大动物皮质组织对淀粉样β（Aβ）积累，神经胶质增生，突触可塑性和血脑屏障破坏的影响。出奇，观察到5XFAD喂养的EOD小鼠皮质的炎症显着增加，这通过小胶质细胞和星形胶质细胞标记的表达得以反映。胶质细胞反应性和/或增殖的增加伴随着促炎细胞因子TNF-α，p38 MAPK和EAAT2的增加以及GAD67的减少。在5XFAD-EOD小鼠的皮层中，与谷氨酸兴奋性毒性相关的NMDA受体亚基2B增加，表明谷氨酸能信号的其他改变。此外，4个月的EOD喂养方案导致5XFAD小鼠的突触可塑性蛋白减少和神经元损伤。然而，EOD喂养方案并不影响5XFAD小鼠皮质的Aβ负荷和血脑屏障通透性。我们的结果表明，EOD喂养方案会加剧阿尔茨海默氏病