Diminished trkA receptor signaling reveals cholinergic-attentional vulnerability of aging.
Diminished trkA receptor signaling reveals cholinergic-attentional vulnerability of aging.
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DOI：
10.1111/ejn.12090
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发表时间：
2013-01
期刊：
影响因子：
--
通讯作者：
Sarter M
中科院分区：
文献类型：
--
作者：
Parikh V;Howe WM;Welchko RM;Naughton SX;D'Amore DE;Han DH;Deo M;Turner DL;Sarter M
基底前脑（BF）胆碱能神经元在病理性衰老过程中异常脆弱的细胞机制仍然难以捉摸。在这里，我们采用基于腺相关病毒载体的 RNA 干扰 (AAV-RNAi) 策略来抑制成年和老年大鼠 Meynert/无名质 (nMB/SI) 基底核中胆碱能神经元的 trkA 受体表达。 trkA 受体表达的抑制选择性地损害老年大鼠的注意力表现。性能与 nMB/SI 中的 trkA 水平相关。 TrkA 敲低既不影响 nMB/SI 胆碱能细胞计数，也不影响老年大鼠中观察到的胆碱能细胞大小的减少。然而，trkA 抑制加剧了与年龄相关的皮质胆碱能过程密度的下降，并减弱了胆碱能神经元释放乙酰胆碱的能力。老年/注射 trkA-AAV 的大鼠体内皮质突触释放乙酰胆碱 (ACh) 的能力也低于老年或年轻对照组，这与它们的注意力表现相关。此外，与年龄相关的皮质proNGF和p75受体水平的增加与载体诱导的trkA受体的丧失相互作用，将NGF信号转变成p75介导的胆碱能表型抑制，从而减弱胆碱能功能并损害注意力表现。这些效应模拟了早期阿尔茨海默病患者胆碱能神经元的异常营养调节和认知障碍。该大鼠模型可用于识别导致老化胆碱能神经元脆弱的机制，以及研究由营养信号破坏触发的神经病理机制。
The cellular mechanisms underlying the exceptional vulnerability of the basal forebrain (BF) cholinergic neurons during pathological aging have remained elusive. Here we employed an adeno-associated viral vector-based RNA interference (AAV-RNAi) strategy to suppress the expression of trkA receptors by cholinergic neurons in the nucleus basalis of Meynert/ substantia innominata (nMB/SI) of adult and aged rats. Suppression of trkA receptor expression impaired attentional performance selectively in aged rats. Performance correlated with trkA levels in the nMB/SI. TrkA knockdown neither affected nMB/SI cholinergic cell counts nor the decrease in cholinergic cell size observed in aged rats. However, trkA suppression augmented an age-related decrease in the density of cortical cholinergic processes and attenuated the capacity of cholinergic neurons to release ACh. The capacity of cortical synapses to release acetylcholine (ACh) in vivo was also lower in aged/trkA-AAV-infused rats than in aged or young controls, and it correlated with their attentional performance. Furthermore, age-related increases in cortical proNGF and p75 receptor levels interacted with the vector-induced loss of trkA receptors to shift NGF signaling toward p75-mediated suppression of the cholinergic phenotype, thereby attenuating cholinergic function and impairing attentional performance. These effects model the abnormal trophic regulation of cholinergic neurons and cognitive impairments in patients with early Alzheimer's disease. This rat model is useful for identifying the mechanisms rendering aging cholinergic neurons vulnerable as well as for studying the neuropathological mechanisms that are triggered by disrupted trophic signaling.
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影响因子：
4
作者：
Ceni, Claire;Kommaddi, Reddy Peera;Barker, Philip A.
通讯作者：
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影响因子：
3.4
作者：
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影响因子：
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通讯作者：
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影响因子：
4.2
作者：
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通讯作者：
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影响因子：
82.9
作者：
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通讯作者：
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