Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
Neurosci Lett. 2010 Mar 8;471(3):129-33. doi: 10.1016/j.neulet.2010.01.023. Epub 2010 Jan 18.
The nerve growth factor (NGF) precursor protein proNGF is the predominant NGF moiety found in the human neocortex and exhibits pro-apoptotic properties when bound to the p75(NTR) neurotrophin receptor in the presence of sortilin, a Vps10p domain trafficking protein. Recently studies have shown that proNGF levels increase in the cortex of people who died with early stage Alzheimer's disease (AD) or with mild cognitive impairment (MCI), a putative prodromal AD stage. In contrast, cortical levels of the high-affinity, pro-survival NGF receptor TrkA are reduced in AD despite stable levels of p75(NTR). These data suggest a stoichiometric shift in proNGF and its receptors which favors proNGF binding of p75(NTR). Whether cortical levels of sortilin are altered during the progression of AD remains unknown. Therefore, we measured sortilin protein levels in postmortem superior frontal and superior temporal cortical tissues derived from Religious Orders Study subjects clinically diagnosed antemortem with no cognitive impairment (NCI), MCI or AD. No changes in frontal or temporal cortical sortilin protein levels occurred across the clinical groups. There was no association between sortilin levels and antemortem cognitive test scores. However, there was a positive association between temporal cortex sortilin levels and severity of neuropathology by Braak and NIA-Reagan diagnoses. The stability of cortical sortilin levels in the face of stable p75(NTR), increased proNGF, and reduced TrkA levels may favor pro-apoptotic proNGF:p75(NTR):sortilin trimeric interactions within the cortex during the earliest stages of AD. These findings are relevant to the development of NGF drug therapy for the treatment of dementia.
神经生长因子（NGF）前体蛋白 proNGF 是人类新皮质中发现的主要 NGF 成分，当与 p75（NTR）神经营养素受体结合并存在分选连接蛋白（Vps10p 结构域运输蛋白）时，表现出促凋亡特性。最近的研究表明，在患有早期阿尔茨海默病（AD）或轻度认知障碍（MCI）的人（AD 的假定前驱阶段）的大脑皮质中，proNGF 水平增加。相比之下，尽管 p75（NTR）水平稳定，但 AD 患者大脑皮质中的高亲和力、促生存 NGF 受体 TrkA 水平降低。这些数据表明 proNGF 及其受体的化学计量发生了变化，有利于 proNGF 与 p75（NTR）结合。在 AD 进展过程中，皮质分选连接蛋白水平是否发生改变仍不清楚。因此，我们测量了来自宗教秩序研究的死后额上和额上皮质组织中分选连接蛋白的水平，这些研究对象在生前临床诊断为无认知障碍（NCI）、MCI 或 AD。在前额或颞叶皮质的临床分组中，分选连接蛋白水平没有变化。分选连接蛋白水平与生前认知测试评分之间没有关联。然而，在颞叶皮质中，分选连接蛋白水平与 Braak 和 NIA-Reagan 诊断的神经病理学严重程度呈正相关。在面对稳定的 p75（NTR）、增加的 proNGF 和减少的 TrkA 水平时，皮质分选连接蛋白水平的稳定性可能有利于 AD 早期阶段大脑皮质中促凋亡的 proNGF:p75（NTR）：分选连接蛋白三聚体相互作用。这些发现与开发 NGF 药物治疗痴呆症有关。
