Fahnestock Margaret, Shekari Arman
Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada.
Neuroscience Graduate Program, McMaster University, Hamilton, ON, Canada.
Front Neurosci. 2019 Feb 22;13:129. doi: 10.3389/fnins.2019.00129. eCollection 2019.
Profound and early basal forebrain cholinergic neuron (BFCN) degeneration is a hallmark of Alzheimer's disease (AD). Loss of synapses between basal forebrain and hippocampal and cortical target tissue correlates highly with the degree of dementia and is thought to be a major contributor to memory loss. BFCNs depend for their survival, connectivity and function on the neurotrophin nerve growth factor (NGF) which is retrogradely transported from its sites of synthesis in the cortex and hippocampus. The form of NGF found in human brain is proNGF. ProNGF binds to the NGF receptors TrkA and p75, but it binds more strongly to p75 and more weakly to TrkA than does mature NGF. This renders proNGF more sensitive to receptor balance than mature NGF. In the healthy brain, where BFCNs express both TrkA and p75, proNGF is neurotrophic, activating TrkA-dependent signaling pathways such as MAPK and Akt-mTOR and eliciting cell survival and neurite outgrowth. However, if TrkA is lost or if p75 is increased, proNGF activates p75-dependent apoptotic pathways such as JNK. This receptor sensitivity serves as a neurotrophic/apoptotic switch that eliminates BFCNs that cannot maintain TrkA/p75 balance and therefore synaptic connections with their targets. TrkA is increasingly lost in mild cognitive impairment (MCI) and AD. In addition, proNGF accumulates at BFCN terminals in cortex and hippocampus, reducing the amount of trophic factor that reaches BFCN cell bodies. The loss of TrkA and accumulation of proNGF occur early in MCI and correlate with cognitive impairment. Increased levels of proNGF and reduced levels of TrkA lead to BFCN neurodegeneration and eventual p75NTR-dependent apoptosis. In addition, in AD BFCNs suffer from reduced TrkA-dependent retrograde transport which reduces neurotrophic support. Thus, BFCNs are particularly vulnerable to AD due to their dependence upon retrograde trophic support from proNGF signaling and transport.
早期基底前脑胆碱能神经元（BFCN）的严重退化是阿尔茨海默病（AD）的一个标志。基底前脑与海马体及皮质靶组织之间突触的丧失与痴呆程度高度相关，并且被认为是导致记忆丧失的主要因素。BFCN的存活、连接性及功能依赖于神经营养因子神经生长因子（NGF），该因子从其在皮质和海马体的合成部位进行逆向运输。在人类大脑中发现的NGF形式是前体NGF（proNGF）。ProNGF与NGF受体TrkA和p75结合，但与成熟NGF相比，它与p75的结合更强，与TrkA的结合更弱。这使得proNGF比成熟NGF对受体平衡更敏感。在健康大脑中，BFCN同时表达TrkA和p75，proNGF具有神经营养作用，激活依赖TrkA的信号通路，如MAPK和Akt - mTOR，并引发细胞存活和神经突生长。然而，如果TrkA缺失或p75增加，proNGF会激活依赖p75的凋亡通路，如JNK。这种受体敏感性充当了一种神经营养/凋亡开关，消除那些无法维持TrkA/p75平衡从而无法与靶标建立突触连接的BFCN。在轻度认知障碍（MCI）和AD中，TrkA逐渐丧失。此外，proNGF在皮质和海马体的BFCN终末积累，减少了到达BFCN细胞体的营养因子数量。TrkA的丧失和proNGF的积累在MCI早期就会出现，并与认知障碍相关。proNGF水平升高和TrkA水平降低会导致BFCN神经退行性变以及最终依赖p75NTR的凋亡。此外，在AD中，BFCN遭受TrkA依赖的逆向运输减少，这降低了神经营养支持。因此，由于BFCN依赖proNGF信号传导和运输的逆向营养支持，它们对AD特别脆弱。
