Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, California 90024, USA.
J Neurosci. 2011 Dec 7;31(49):17800-10. doi: 10.1523/JNEUROSCI.3878-11.2011.
Aging-related cognitive declines are well documented in humans and animal models. Yet the synaptic and molecular mechanisms responsible for cognitive aging are not well understood. Here we demonstrated age-dependent deficits in long-term synaptic plasticity and loss of dendritic spines in the hippocampus of aged Fisher 344 rats, which were closely associated with reduced histone acetylation, upregulation of histone deacetylase (HDAC) 2, and decreased expression of a histone acetyltransferase. Further analysis showed that one of the key genes affected by such changes was the brain-derived neurotrophic factor (Bdnf) gene. Age-dependent reductions in H3 and H4 acetylation were detected within multiple promoter regions of the Bdnf gene, leading to a significant decrease in BDNF expression and impairment of downstream signaling in the aged hippocampus. These synaptic and signaling deficits could be rescued by enhancing BDNF and trkB expression via HDAC inhibition or by directly activating trkB receptors with 7,8-dihydroxyflavone, a newly identified, selective agonist for trkB. Together, our findings suggest that age-dependent declines in chromatin histone acetylation and the resulting changes in BDNF expression and signaling are key mechanisms underlying the deterioration of synaptic function and structure in the aging brain. Furthermore, epigenetic or pharmacological enhancement of BDNF-trkB signaling could be a promising strategy for reversing cognitive aging.
衰老相关的认知能力下降在人类和动物模型中都有明确的记录。然而，导致认知衰老的突触和分子机制还没有被很好地理解。在这里，我们在老年 Fisher 344 大鼠的海马体中观察到了与年龄相关的长期突触可塑性缺陷和树突棘丢失，这与组蛋白乙酰化减少、组蛋白去乙酰化酶（HDAC）2 上调以及组蛋白乙酰转移酶表达减少密切相关。进一步的分析表明，受这些变化影响的关键基因之一是脑源性神经营养因子（BDNF）基因。在 Bdnf 基因的多个启动子区域内检测到与年龄相关的 H3 和 H4 乙酰化减少，导致 BDNF 表达显著减少，并损害了老年海马体中的下游信号转导。通过抑制 HDAC 来增强 BDNF 和 trkB 的表达，或通过使用新鉴定的 trkB 的选择性激动剂 7,8-二羟基黄酮直接激活 trkB 受体，可挽救这些突触和信号转导缺陷。总之，我们的研究结果表明，与年龄相关的染色质组蛋白乙酰化的下降以及由此导致的 BDNF 表达和信号转导的变化是导致衰老大脑中突触功能和结构恶化的关键机制。此外，BDNF-trkB 信号的表观遗传或药理学增强可能是逆转认知衰老的有前途的策略。
