Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada; Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Neurobiol Aging. 2018 Jul;67:10-20. doi: 10.1016/j.neurobiolaging.2018.03.002. Epub 2018 Mar 9.
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.
基底前脑胆碱能神经元（BFCNs）在阿尔茨海默病（AD）中的退化导致认知障碍。大脑皮层分泌的神经生长因子（NGF）对于 BFCNs 的表型维持是必需的。AD 与 NGF 代谢紊乱有关，导致成熟 NGF 水平降低，其前体 proNGF 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类似 AD 的 BFCN 逆行性退化。通过逆行标记和定量细胞成像的组合，我们可以证明抑制皮质 proNGF 成熟会导致 BFCN 萎缩、NGF 受体 p75 神经生长因子受体和原肌球蛋白受体激酶 A 的下调以及胆碱乙酰转移酶蛋白表达减少。Sortilin 水平的短暂增加和与 p75 神经生长因子受体的持续共定位表明 proNGF 参与了这个退化过程。这项研究表明，细胞外 proNGF 成熟的损伤足以导致 BFCNs 的体树突逆行性退化。
