Mufson Elliott J, Counts Scott E, Fahnestock Margaret, Ginsberg Stephen D
Department of Neurological Sciences, Rush University Medical School, Chicago, IL 60612, USA.
Curr Alzheimer Res. 2007 Sep;4(4):340-50. doi: 10.2174/156720507781788855.
Cholinergic nucleus basalis (NB) neurons provide the major cholinergic innervation to the cortical mantle, are selectively vulnerable in late stage Alzheimer's disease (AD) and require the neurotrophin, nerve growth factor (NGF) and its receptors (TrkA and p75(NTR)), for their survival. The molecular events underlying the demise of these neurons in AD were investigated using tissue harvested from participants in a longitudinal clinical pathological study of aging and AD who agreed to an annual clinical evaluation providing a categorization of no cognitive impairment (NCI), mild cognitive impairment (MCI) or AD and postmortem brain donation. Although the number of choline acetyltransferase (ChAT)-positive neurons was unchanged, TrkA and p75(NTR) receptor-containing neurons, which co-localize with ChAT, were significantly reduced in the NB of subjects with MCI and AD compared to those with NCI. These observations indicate a phenotypic down-regulation rather than frank NB neuronal degeneration in MCI. Expression profiling of single cholinergic NB neurons revealed TrkA but not p75(NTR) mRNA is reduced in MCI, suggesting that decreased neurotrophin responsiveness may be an early biomarker for AD. The NGF precursor molecule, proNGF, is increased in the cortex in MCI and AD. Since proNGF accumulates in the presence of reduced cortical TrkA and sustained levels of p75(NTR), a shift in the balance between cell survival and death molecules may occur in prodromal AD. Coincident with these phenomena, brain derived neurotrophic factor (BDNF) and its precursor molecule, proBDNF, are reduced in the MCI cortex, potentially depriving CBF neurons of additional trophic factor support. Moreover, there is a shift in the ratio of 3 repeat tau to 4 repeat tau gene expression, whereas total tau message is stable in NB neurons during the disease process. These data suggest there is a shift in cholinotrophic molecular events in MCI and early AD which may lead to cell dysfunction and eventual cell death over the course of the disease. These findings support the concept that from a neurotrophic pathobiologic perspective, MCI is already early AD.
胆碱能基底核（NB）神经元为皮质提供主要的胆碱能神经支配，在晚期阿尔茨海默病（AD）中选择性易损，并且其存活需要神经营养因子、神经生长因子（NGF）及其受体（TrkA和p75（NTR））。使用从参与衰老和AD纵向临床病理研究的参与者身上获取的组织，对这些神经元在AD中死亡的分子事件进行了研究，这些参与者同意每年进行临床评估，评估结果分为无认知障碍（NCI）、轻度认知障碍（MCI）或AD，并在死后捐赠大脑。尽管胆碱乙酰转移酶（ChAT）阳性神经元的数量没有变化，但与ChAT共定位的含TrkA和p75（NTR）受体的神经元，在MCI和AD患者的NB中与NCI患者相比显著减少。这些观察结果表明在MCI中存在表型下调而非明显的NB神经元变性。对单个胆碱能NB神经元的表达谱分析显示，MCI中TrkA mRNA减少而p75（NTR）mRNA未减少，这表明神经营养因子反应性降低可能是AD的早期生物标志物。NGF前体分子proNGF在MCI和AD的皮质中增加。由于proNGF在皮质TrkA减少和p75（NTR）水平持续存在的情况下积累，则在AD前驱期可能会发生细胞存活和死亡分子之间平衡的转变。与这些现象一致的是，脑源性神经营养因子（BDNF）及其前体分子proBDNF在MCI皮质中减少，这可能会使胆碱能基底核神经元失去额外的营养因子支持。此外，3重复tau与4重复tau基因表达的比例发生了变化，而在疾病过程中NB神经元中的总tau信息是稳定的。这些数据表明，MCI和早期AD中胆碱能营养分子事件发生了转变，这可能在疾病过程中导致细胞功能障碍并最终导致细胞死亡。这些发现支持了这样一种观点，即从神经营养病理生物学角度来看，MCI已经是早期AD。
