Yousef Hanadie, Morgenthaler Adam, Schlesinger Christina, Bugaj Lukasz, Conboy Irina M, Schaffer David V
Department of Molecular and Cell Biology; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Center for Tissue Regeneration, Repair and Restoration, Veterans Administration Palo Alto Health Care System, Palo Alto, CA 94304, USA.
Stem Cells. 2015 May;33(5):1577-88. doi: 10.1002/stem.1943.
Hippocampal neurogenesis, the product of resident neural stem cell proliferation and differentiation, persists into adulthood but decreases with organismal aging, which may contribute to the age-related decline in cognitive function. The mechanisms that underlie this decrease in neurogenesis are not well understood, although evidence in general indicates that extrinsic changes in an aged stem cell niche can contribute to functional decline in old stem cells. Bone morphogenetic protein (BMP) family members are intercellular signaling proteins that regulate stem and progenitor cell quiescence, proliferation, and differentiation in various tissues and are likewise critical regulators of neurogenesis in young adults. Here, we establish that BMP signaling increases significantly in old murine hippocampi and inhibits neural progenitor cell proliferation. Furthermore, direct in vivo attenuation of BMP signaling via genetic and transgenic perturbations in aged mice led to elevated neural stem cell proliferation, and subsequent neurogenesis, in old hippocampi. Such advances in our understanding of mechanisms underlying decreased hippocampal neurogenesis with age may offer targets for the treatment of age-related cognitive decline.
海马神经发生是驻留神经干细胞增殖和分化的产物，持续至成年期，但会随着机体衰老而减少，这可能是导致与年龄相关的认知功能衰退的原因之一。尽管总体证据表明，衰老的干细胞微环境中的外在变化可能导致老年干细胞功能衰退，但神经发生减少的潜在机制尚未完全明确。骨形态发生蛋白（BMP）家族成员是细胞间信号蛋白，可调节各种组织中的干细胞和祖细胞的静止、增殖和分化，同样也是年轻成年个体神经发生的关键调节因子。在此，我们证实老年小鼠海马体中的BMP信号显著增强，并抑制神经祖细胞增殖。此外，通过对老年小鼠进行基因和转基因干扰，直接在体内减弱BMP信号，可导致老年海马体中神经干细胞增殖增加以及随后的神经发生增加。我们对海马神经发生随年龄增长而减少的潜在机制的这种理解进展，可能为治疗与年龄相关的认知衰退提供靶点。
