Aging and a peripheral immune challenge interact to reduce mature brain-derived neurotrophic factor and activation of TrkB, PLCgamma1, and ERK in hippocampal synaptoneurosomes.
Aging and a peripheral immune challenge interact to reduce mature brain-derived neurotrophic factor and activation of TrkB, PLCgamma1, and ERK in hippocampal synaptoneurosomes.
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DOI：
10.1523/jneurosci.5818-10.2011
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发表时间：
2011-03-16
期刊：
影响因子：
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通讯作者：
Patterson SL
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文献类型：
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作者：
Cortese GP;Barrientos RM;Maier SF;Patterson SL
由于尚不清楚的原因，衰老显着增加了大脑应对挑战性生活事件的脆弱性。高功能老年人在手术、感染或受伤等炎症事件后通常会经历显着的认知能力下降。我们在啮齿类动物中模拟了这种现象，并且之前报道过外周免疫挑战（腹膜内注射活大肠杆菌）选择性地破坏老年（24 个月大）而非年轻（3 个月大）F344xBN 大鼠海马依赖记忆的巩固。最近，我们已经证明，这种感染引起的记忆缺陷是由海马体中持久突触可塑性的选择性缺陷所反映的。有趣的是，这些缺陷以长期记忆和突触可塑性的形式出现，已知强烈依赖于 BDNF。在这里，我们开始检验这样的假设：衰老和感染的结合可能会破坏海马 BDNF 蛋白的产生或加工，从而降低 BDNF 在突触部位可塑性相关过程中的可用性。我们发现，在老年动物感染后制备的海马突触神经体的蛋白质印迹中，成熟的 BDNF 显着减少。这种减少可以通过小脑延髓池内施用抗炎细胞因子 IL-1Ra 来阻断。在这些突触神经体中，泛神经营养蛋白受体 p75NTR 和 BDNF 受体 TrkB 的水平没有显着改变，但 TrkB 的磷酸化以及下游 PLCγ1 和 ERK 的激活减弱——观察结果与 mBDNF 激活 TrkB 信号传导的可用性降低一致。这些数据表明，炎症引起的突触 BDNF 减少可能会导致炎症引起的长期记忆破坏和衰老过程中的突触可塑性。
For reasons that are not well understood, aging significantly increases brain vulnerability to challenging life events. High functioning older individuals often experience significant cognitive decline after an inflammatory event such as surgery, infection or injury. We have modeled this phenomenon in rodents, and have previously reported that a peripheral immune challenge (intraperitoneal injection of live E. coli) selectively disrupts consolidation of hippocampus-dependent memory in aged (24-month-old), but not young (3-month-old) F344xBN rats. More recently, we have demonstrated that this infection-evoked memory deficit is mirrored by a selective deficit in long-lasting synaptic plasticity in the hippocampus. Interestingly, these deficits occur in forms of long-term memory and synaptic plasticity known to be strongly dependent on BDNF. Here, we begin to test the hypothesis that the combination of aging and an infection might disrupt production or processing of BDNF protein in the hippocampus, decreasing the availability of BDNF for plasticity-related processes at synaptic sites. We find that mature BDNF is markedly reduced in Western blots of hippocampal synaptoneurosomes prepared from aged animals following infection. This reduction is blocked by intra-cisterna magna administration of the anti-inflammatory cytokine IL-1Ra. Levels of the pan-neurotrophin receptor p75NTR and the BDNF receptor TrkB are not significantly altered in these synaptoneurosomes, but phosphorylation of TrkB and downstream activation of PLCγ1 and ERK are attenuated – observations consistent with reduced availability of mBDNF to activate TrkB signaling. These data suggest that inflammation-evoked reductions in BDNF at synapses might contribute to inflammation-evoked disruptions in long-term memory and synaptic plasticity in aging.