PDF(Pubmed)
Abstract：
Brain pathological changes impair cognition early in disease etiology. There is an urgent need to understand aging-linked mechanisms of early memory loss to develop therapeutic strategies and prevent the development of cognitive impairment. Tusc2 is a mitochondrial-resident protein regulating Ca2+ fluxes to and from mitochondria impacting overall health. We previously reported that Tusc2-/- female mice develop chronic inflammation and age prematurely, causing age- and sex-dependent spatial memory deficits at 5 months old. Therefore, we investigated Tusc2-dependent mechanisms of memory impairment in 4-month-old mice, comparing changes in resident and brain-infiltrating immune cells. Interestingly, Tusc2-/- female mice demonstrated a pro-inflammatory increase in astrocytes, expression of IFN-γ in CD4+ T cells and Granzyme-B in CD8+T cells. We also found fewer FOXP3+ T-regulatory cells and Ly49G+ NK and Ly49G+ NKT cells in female Tusc2-/- brains, suggesting a dampened anti-inflammatory response. Moreover, Tusc2-/- hippocampi exhibited Tusc2- and sex-specific protein changes associated with brain plasticity, including mTOR activation, and Calbindin and CamKII dysregulation affecting intracellular Ca2+ dynamics. Overall, the data suggest that dysregulation of Ca2+-dependent processes and a heightened pro-inflammatory brain microenvironment in Tusc2-/- mice could underlie cognitive impairment. Thus, strategies to modulate the mitochondrial Tusc2- and Ca2+- signaling pathways in the brain should be explored to improve cognitive health.
摘要：
脑部病理变化在疾病病因的早期损害认知。迫切需要了解与衰老相关的早期记忆丧失机制，以制定治疗策略并预防认知障碍的发展。Tusc2是一种线粒体驻留蛋白，可调节进出线粒体的Ca2通量，从而影响整体健康。我们之前报道了Tusc2-/-雌性小鼠发生慢性炎症和过早衰老，在5个月大时导致年龄和性别依赖性空间记忆缺陷。因此,我们研究了4月龄小鼠记忆障碍的Tusc2依赖性机制，比较常驻和脑浸润免疫细胞的变化。有趣的是,Tusc2-/-雌性小鼠表现出星形胶质细胞的促炎性增加，IFN-γ在CD4+T细胞中的表达和颗粒酶-B在CD8+T细胞中的表达。我们还发现女性Tusc2-/-脑中FOXP3+T调节细胞和Ly49G+NK和Ly49G+NKT细胞较少，提示抗炎反应减弱。此外，Tusc2-/-海马表现出与脑可塑性相关的Tusc2-和性别特异性蛋白变化，包括mTOR激活,以及Calbindin和CamKII失调影响细胞内Ca2动态。总的来说,数据提示Tusc2-/-小鼠中Ca2+依赖性过程的失调和促炎脑微环境的增强可能是认知障碍的基础.因此，应该探索调节大脑中线粒体Tusc2-和Ca2+信号通路的策略，以改善认知健康。
