Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
J Alzheimers Dis. 2024;98(3):925-940. doi: 10.3233/JAD-231117.
Caloric restriction (CR) has been recognized for its benefits in delaying age-related diseases and extending lifespan. While its effects on amyloid pathology in Alzheimer's disease (AD) mouse models are well-documented, its effects on tauopathy, another hallmark of AD, are less explored.
To assess the impact of a short-term 30% CR regimen on age-dependent spatial learning deficits and pathological features in a tauopathy mouse model.
We subjected male PS19 tau P301S (hereafter PS19) and age-matched wildtype mice from two age cohorts (4.5 and 7.5 months old) to a 6-week 30% CR regimen. Spatial learning performance was assessed using the Barnes Maze test. Tau pathology, neuroinflammation, hippocampal cell proliferation, and neurogenesis were evaluated in the older cohort by immunohistochemical staining and RT-qPCR.
CR mitigated age-dependent spatial learning deficits in PS19 mice but exhibited limited effects on tau pathology and the associated neuroinflammation. Additionally, we found a decrease in hippocampal cell proliferation, predominantly of Iba1+ cells.
Our findings reinforce the cognitive benefits conferred by CR despite its limited modulation of disease pathology. Given the pivotal role of microglia in tau-driven pathology, the observed reduction in Iba1+ cells under CR suggests potential therapeutic implications, particularly if CR would be introduced early in disease progression.
热量限制（CR）已被公认可延缓与年龄相关的疾病并延长寿命。虽然它对阿尔茨海默病（AD）小鼠模型中淀粉样蛋白病理的影响已有充分记录，但对另一个 AD 标志——tau 病的影响则研究较少。
评估短期 30% CR 方案对 tau 病小鼠模型中与年龄相关的空间学习缺陷和病理特征的影响。
我们将雄性 PS19 tau P301S（以下简称 PS19）和年龄匹配的野生型小鼠分为两个年龄组（4.5 个月和 7.5 个月），进行为期 6 周的 30% CR 方案。使用 Barnes 迷宫测试评估空间学习表现。通过免疫组织化学染色和 RT-qPCR 在较年长的队列中评估 tau 病理、神经炎症、海马细胞增殖和神经发生。
CR 减轻了 PS19 小鼠中与年龄相关的空间学习缺陷，但对 tau 病理和相关神经炎症的影响有限。此外，我们发现海马细胞增殖减少，主要是 Iba1+细胞。
我们的发现强化了 CR 带来的认知益处，尽管它对疾病病理的调节作用有限。鉴于小胶质细胞在 tau 驱动的病理中的关键作用，CR 下观察到的 Iba1+细胞减少表明存在潜在的治疗意义，特别是如果在疾病进展早期引入 CR。
