Effects of sustained proNGF blockade on attentional capacities in aged rats with compromised cholinergic system.
Effects of sustained proNGF blockade on attentional capacities in aged rats with compromised cholinergic system.
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DOI：
10.1016/j.neuroscience.2013.12.042
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发表时间：
2014-03-07
期刊：
影响因子：
3.3
通讯作者：
Parikh, V.
中科院分区：
文献类型：
--
作者：
Yegla, B.;Parikh, V.
通过trkA受体的神经生长因子（NGF）信号传导的中断损害基底前脑（BF）胆碱能系统的完整性，在阿尔茨海默病（AD）中产生认知，特别是注意力障碍。虽然正常衰老被认为是AD的危险因素，但衰老胆碱能系统对trkA干扰的选择性脆弱性的机制尚不清楚。proNGF是一种对p75受体具有更高亲和力的前神经营养因子，其水平随着年龄的增长而增加。本研究的目的是测试的假设，胆碱能和注意力功能障碍的老年大鼠减少BF trkA受体发生由于过度激活的内源性proNGF信号。我们采用了一种病毒载体，产生trkA的shRNA抑制trkA受体在皮层胆碱能神经元的老年大鼠。BF trkA抑制损害了动物在持续注意任务（SAT）和SAT的认知负荷分心物版本（dSAT）中的信号试验的表现，并且这些缺陷通过proNGF抗体的慢性脑室内施用而正常化。此外，去极化诱发的ACh释放和皮质胆碱能纤维的密度在这些动物中部分恢复。然而，由于在非信号试验中表现受损，在trkA敲低大鼠中proNGF阻断后，反映整体表现的SAT/dSAT评分没有改善。持续的proNGF阻断单独没有改变基线注意力的表现，但在挑战性的条件下产生中度损害。总的来说，我们的研究结果表明，禁止proNGF-p75信号可能会对注意力产生一些有益的影响，特别是当BF trkA信号被废除。然而，内源性神经生长因子原也可能具有神经营养作用，阻断这种神经营养因子原可能无法完全改善AD中的注意力障碍，并可能阻碍正常衰老中高认知负荷期间的表现。
Disruption in nerve growth factor (NGF) signaling via trkA receptors compromises the integrity of the basal forebrain (BF) cholinergic system, yielding cognitive, specifically attentional, impairments in Alzheimer’s disease (AD). Although normal aging is considered a risk factor for AD, the mechanisms underlying the selective vulnerability of the aging cholinergic system to trkA disruption is not clear. The levels of proNGF, a proneurotrophin that possesses higher affinity for p75 receptors, increase in aging. The present study was designed to test the hypothesis that cholinergic and attentional dysfunction in aged rats with reduced BF trkA receptors occurs due to the overactivation of endogenous proNGF signaling. We employed a viral vector that produced trkA shRNA to suppress trkA receptors in the corticopetal cholinergic neurons of aged rats. BF trkA suppression impaired animals’ performance on signal trials in both the sustained attention task (SAT) and the cognitively-taxing distractor version of SAT (dSAT) and these deficits were normalized by chronic intracerebroventricular administration of proNGF antibody. Moreover, depolarization-evoked ACh release and the density of cortical cholinergic fibers were partially restored in these animals. However, SAT/dSAT scores reflecting overall performance did not improve following proNGF blockade in trkA knockdown rats due to impaired performance in non-signal trials. Sustained proNGF blockade alone did not alter baseline attentional performance but produced moderate impairments during challenging conditions. Collectively, our findings indicate that barring proNGF-p75 signaling may exert some beneficial effects on attentional capacities specifically when BF trkA signaling is abrogated. However, endogenous proNGF may also possess neurotrophic effects and blockade of this proneurotrophin may not completely ameliorate attentional impairments in AD and potentially hinder performance during periods of high cognitive load in normal aging.
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影响因子：
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作者：
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通讯作者：
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