Counts Scott E, Mufson Elliott J
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612, USA.
J Neuropathol Exp Neurol. 2005 Apr;64(4):263-72. doi: 10.1093/jnen/64.4.263.
Dysfunction of nerve growth factor (NGF) and its high (TrkA) and low (p75NTR) affinity receptors has been suggested to underlie the selective degeneration of the nucleus basalis (NB) cholinergic cortical projection neurons in end stage Alzheimer disease (AD). Whether the NGF system is dysfunctional during the prodromal stages of AD has only recently been evaluated. Surprisingly, the number of choline acetyltransferase-containing neurons remains stable despite a significant reduction in NGF receptor-positive cells in people with mild cognitive impairment (MCI), suggesting a phenotypic NGF receptor downregulation but not a frank loss of NB neurons during prodromal AD. Moreover, there is a loss of cortical TrkA in the face of stable p75NTR and increased proNGF levels, the precursor molecule of mature NGF, in early AD. Depending upon the cellular context these changes may result in increased pro-apoptotic signaling, cell survival, or a defect in retrograde transport mechanisms. Alterations in NGF and its receptors within the cholinotrophic NB system in early AD suggest that NGF-mediated cell signaling is required for the longterm survival of these neurons. Therapeutic neurotrophic intervention might delay or prevent NB neuron degeneration and preserve cholinergic cortical function during prodromal AD.
神经生长因子（NGF）及其高亲和力受体（TrkA）和低亲和力受体（p75NTR）功能障碍被认为是晚期阿尔茨海默病（AD）中基底核（NB）胆碱能皮质投射神经元选择性变性的基础。直到最近才评估了AD前驱期NGF系统是否功能失调。令人惊讶的是，尽管轻度认知障碍（MCI）患者的NGF受体阳性细胞显著减少，但含胆碱乙酰转移酶的神经元数量保持稳定，这表明在前驱期AD中存在NGF受体的表型下调，但NB神经元并未明显丧失。此外，在早期AD中，面对稳定的p75NTR和成熟NGF的前体分子proNGF水平升高，皮质TrkA会减少。根据细胞环境的不同，这些变化可能导致促凋亡信号增加、细胞存活或逆行转运机制缺陷。早期AD中胆碱能营养性NB系统内NGF及其受体的改变表明，NGF介导的细胞信号传导是这些神经元长期存活所必需的。治疗性神经营养干预可能会延迟或预防前驱期AD中NB神经元的变性，并保留胆碱能皮质功能。
