Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305;
Proc Natl Acad Sci U S A. 2019 Jun 18;116(25):12524-12533. doi: 10.1073/pnas.1902672116. Epub 2019 Jun 3.
Aging drives a progressive decline in cognition and decreases synapse numbers and synaptic function in the brain, thereby increasing the risk for neurodegenerative disease. Pioneering studies showed that introduction of blood from young mice into aged mice reversed age-associated cognitive impairments and increased synaptic connectivity in brain, suggesting that young blood contains specific factors that remediate age-associated decreases in brain function. However, whether such factors in blood from young animals act directly on neurons to enhance synaptic connectivity, or whether they act by an indirect mechanism remains unknown. Moreover, which factors in young blood mediate cognitive improvements in old mice is incompletely understood. Here, we show that serum extracted from the blood of young but not old mice, when applied to neurons transdifferentiated from human embryonic stem cells, directly increased dendritic arborization, augmented synapse numbers, doubled dendritic spine-like structures, and elevated synaptic -methyl-d-aspartate (NMDA) receptors, thereby increasing synaptic connectivity. Mass spectrometry revealed that thrombospondin-4 (THBS4) and SPARC-like protein 1 (SPARCL1) were enriched in serum from young mice. Strikingly, recombinant THBS4 and SPARCL1 both increased dendritic arborization and doubled synapse numbers in cultured neurons. In addition, SPARCL1 but not THBS4 tripled NMDA receptor-mediated synaptic responses. Thus, at least two proteins enriched in young blood, THBS4 and SPARCL1, directly act on neurons as synaptogenic factors. These proteins may represent rejuvenation factors that enhance synaptic connectivity by increasing dendritic arborization, synapse formation, and synaptic transmission.
衰老会导致认知能力逐渐下降，减少大脑中的突触数量和突触功能，从而增加神经退行性疾病的风险。开创性的研究表明，将年轻小鼠的血液引入老年小鼠体内，可逆转与年龄相关的认知障碍，并增加大脑中的突触连接，这表明年轻血液中含有特定的因子，可以修复与年龄相关的大脑功能下降。然而，年轻动物血液中的这些因子是直接作用于神经元以增强突触连接，还是通过间接机制起作用尚不清楚。此外，年轻血液中的哪些因子介导老年小鼠的认知改善仍不完全清楚。在这里，我们表明，来自年轻但不是老年小鼠的血液提取的血清，当应用于从人类胚胎干细胞分化而来的神经元时，直接增加树突分支，增加突触数量，使树突棘样结构增加一倍，并提高突触 -N- 甲基-D-天冬氨酸 (NMDA) 受体，从而增加突触连接。质谱分析显示，血小板反应蛋白 4 (THBS4) 和 SPARC 样蛋白 1 (SPARCL1) 在年轻小鼠的血清中含量丰富。引人注目的是，重组 THBS4 和 SPARCL1 均增加了培养神经元中的树突分支和突触数量。此外，SPARCL1 而非 THBS4 使 NMDA 受体介导的突触反应增加了两倍。因此，至少有两种在年轻血液中丰富的蛋白质，THBS4 和 SPARCL1，作为促突触形成因子直接作用于神经元。这些蛋白质可能代表通过增加树突分支、突触形成和突触传递来增强突触连接的恢复因子。
