Compromise of cortical proNGF maturation causes selective retrograde atrophy in cholinergic nucleus basalis neurons
Compromise of cortical proNGF maturation causes selective retrograde atrophy in cholinergic nucleus basalis neurons
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DOI：
10.1016/j.neurobiolaging.2018.03.002
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发表时间：
2018-07-01
影响因子：
4.2
通讯作者：
Cuello, A. Claudio
中科院分区：
文献类型：
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作者：
Allard, Simon;Jacobs, Marie L.;Cuello, A. Claudio
阿尔茨海默病（AD）患者基底前脑胆碱能神经元（BFCNs）变性导致认知障碍。大脑皮层分泌的神经生长因子（NGF）是脑啡肽神经网络表型维持所必需的。AD与NGF代谢紊乱有关，导致成熟NGF水平降低及其前体proNGF的积累。我们之前描述过，在大鼠中，这种神经营养失衡足以诱导皮质胆碱能突触的丧失。在本研究中，我们研究了这种神经营养失衡是否会导致BFCNs发生ad样逆行变性。通过逆行标记和定量细胞成像的结合，我们可以证明抑制皮质proNGF成熟导致BFCNs萎缩，NGF受体p75神经营养因子受体和原肌球蛋白受体激酶a下调，以及胆碱乙酰转移酶蛋白表达减少。sortilin水平的短暂升高和p75神经营养因子受体的持续共定位表明proNGF参与了这一退行性过程。本研究表明，proNGF细胞外成熟的损伤足以引起BFCNs的体突逆行变性。(C) 2018爱思唯尔公司版权所有。
The degeneration of basal forebrain cholinergic neurons (BFCNs) in Alzheimer's disease (AD) contributes to cognitive impairment. Nerve growth factor (NGF) secreted in the cerebral cortex is necessary for the phenotypic maintenance of BFCNs. AD is associated with disturbances in NGF metabolism, leading to reduced mature NGF levels and to an accumulation of its precursor, proNGF. We previously described that, in rats, this neurotrophic imbalance is sufficient to induce a loss of cortical cholinergic synapses. In the present study, we investigated whether this neurotrophic imbalance can produce an AD-like retrograde degeneration of BFCNs. Using a combination of retrograde labeling and quantitative cell imaging, we could demonstrate that inhibiting cortical proNGF maturation results in an atrophy of BFCNs, a downregulation of the NGF receptors p75 neurotrophin receptor and tropomyosin receptor kinase A, and a reduction in choline acetyltransferase protein expression. The transient increase in sortilin levels and the sustained colocalization with p75 neurotrophin receptor suggest a participation of proNGF in this degenerative process. This study demonstrates that impairments in the extracellular maturation of proNGF are sufficient to cause a somatodendritic retrograde degeneration of the BFCNs. (C) 2018 Elsevier Inc. All rights reserved.