Sanchez Diego, Bajo-Grañeras Raquel, Del Caño-Espinel Manuela, Garcia-Centeno Rosa, Garcia-Mateo Nadia, Pascua-Maestro Raquel, Ganfornina Maria D
Instituto de Biología y Genética Molecular-Departamento de Bioquímica y Biología Molecular y Fisiología, Universidad de Valladolid-CSIC, Valladolid, Spain.
Instituto de Biología y Genética Molecular-Departamento de Bioquímica y Biología Molecular y Fisiología, Universidad de Valladolid-CSIC, Valladolid, Spain.
Exp Gerontol. 2015 Jul;67:19-47. doi: 10.1016/j.exger.2015.04.003. Epub 2015 Apr 11.
A detailed knowledge of the mechanisms underlying brain aging is fundamental to understand its functional decline and the baseline upon which brain pathologies superimpose. Endogenous protective mechanisms must contribute to the adaptability and plasticity still present in the healthy aged brain. Apolipoprotein D (ApoD) is one of the few genes with a consistent and evolutionarily conserved up-regulation in the aged brain. ApoD protecting roles upon stress or injury are well known, but a study of the effects of ApoD expression in the normal aging process is still missing. Using an ApoD-knockout mouse we analyze the effects of ApoD on factors contributing to the functional maintenance of the aged brain. We focused our cellular and molecular analyses in the cortex and hippocampus at an age representing the onset of senescence where mortality risks are below 25%, avoiding bias towards long-lived animals. Lack of ApoD causes a prematurely aged brain without altering lifespan. Age-dependent hyperkinesia and memory deficits are accompanied by differential molecular effects in the cortex and hippocampus. Transcriptome analyses reveal distinct effects of ApoD loss on the molecular age-dependent patterns of the cortex and hippocampus, with different cell-type contributions to age-regulated gene expression. Markers of glial reactivity, proteostasis, and oxidative and inflammatory damage reveal early signs of aging and enhanced brain deterioration in the ApoD-knockout brain. The lack of ApoD results in an age-enhanced significant reduction in neuronal calcium-dependent functionality markers and signs of early reduction of neuronal numbers in the cortex, thus impinging upon parameters clearly differentiating neurodegenerative conditions from healthy brain aging. Our data support the hypothesis that the physiological increased brain expression of ApoD represents a homeostatic anti-aging mechanism.
深入了解大脑衰老背后的机制是理解其功能衰退以及脑部病变叠加的基线的基础。内源性保护机制必定有助于健康老龄大脑中仍存在的适应性和可塑性。载脂蛋白D（ApoD）是少数在老龄大脑中呈现持续且进化保守上调的基因之一。ApoD在应激或损伤时的保护作用已为人熟知，但关于ApoD表达在正常衰老过程中的影响的研究仍付诸阙如。我们使用ApoD基因敲除小鼠分析了ApoD对有助于老龄大脑功能维持的因素的影响。我们将细胞和分子分析聚焦于代表衰老起始阶段的年龄时的皮质和海马体，此时死亡风险低于25%，避免了对长寿动物的偏向性。缺乏ApoD会导致大脑过早衰老，但不会改变寿命。与年龄相关的运动亢进和记忆缺陷伴随着皮质和海马体中不同的分子效应。转录组分析揭示了ApoD缺失对皮质和海马体分子年龄依赖性模式的不同影响，不同细胞类型对年龄调节基因表达有不同贡献。神经胶质反应性、蛋白质稳态以及氧化和炎症损伤的标志物揭示了ApoD基因敲除大脑中衰老的早期迹象和脑部恶化加剧。缺乏ApoD导致与年龄相关的神经元钙依赖性功能标志物显著降低，以及皮质中神经元数量早期减少的迹象，从而影响了将神经退行性疾病与健康大脑衰老区分开来的参数。我们的数据支持这样的假设，即大脑中ApoD的生理性表达增加代表一种稳态抗衰老机制。
