Department of Psychology and Neuroscience Program, Temple University, Philadelphia, PA 19122, USA.
Eur J Neurosci. 2013 Jan;37(2):278-93. doi: 10.1111/ejn.12090. Epub 2012 Dec 11.
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 tropomyosin-related kinase A (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 acetylcholine (ACh). The capacity of cortical synapses to release 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.
基底前脑（BF）胆碱能神经元在病理性衰老过程中表现出异常脆弱性的细胞机制仍未被揭示。在这里，我们采用腺相关病毒载体的 RNA 干扰（AAV-RNAi）策略，通过基底核 Meynert/无名质（nMB/SI）中的胆碱能神经元来抑制原肌球蛋白相关激酶 A（trkA）受体的表达，成年和老年大鼠。trkA 受体表达的抑制选择性地损害了老年大鼠的注意力表现。表现与 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减少。然而，trkA 抑制增强了与年龄相关的皮质胆碱能过程密度的降低，并减弱了胆碱能神经元释放乙酰胆碱（ACh）的能力。皮质突触在体内释放 ACh 的能力在老年/trkA-AAV 输注大鼠中也低于老年或年轻对照大鼠，并且与它们的注意力表现相关。此外，皮质原神经生长因子（proNGF）和 p75 受体水平的年龄相关性增加与载体诱导的 trkA 受体丧失相互作用，将 NGF 信号转导转向 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。这些效应模拟了胆碱能神经元的异常营养调节和早期阿尔茨海默病患者的认知障碍。这种大鼠模型可用于鉴定使衰老胆碱能神经元脆弱的机制，并研究由营养信号中断引发的神经病理学机制。
