Perez Sylvia E, He Bin, Nadeem Muhammad, Wuu Joanne, Scheff Stephen W, Abrahamson Eric E, Ikonomovic Milos D, Mufson Elliott J
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois.
Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida.
Biol Psychiatry. 2015 Apr 15;77(8):693-703. doi: 10.1016/j.biopsych.2013.12.016. Epub 2014 Jan 11.
Reduction of precuneus choline acetyltransferase activity co-occurs with greater beta-amyloid (Aβ) in Alzheimer's disease (AD). Whether this cholinergic deficit is associated with alteration in nerve growth factor (NGF) signaling and its relation to Aβ plaque and neurofibrillary tangle (NFT) pathology during disease onset is unknown.
Precuneus NGF upstream and downstream signaling levels relative to Aβ and NFT pathology were evaluated using biochemistry and histochemistry in 62 subjects with a premortem diagnosis of non-cognitively impaired (NCI; n = 23), mild cognitive impairment (MCI; n = 21), and mild to moderate AD (n = 18).
Immunoblots revealed increased levels of proNGF in AD subjects but not MCI subjects, whereas cognate receptors were unchanged. There were no significant differences in protein level for the downstream survival kinase-signaling proteins Erk and phospho-Erk among groups. Apoptotic phospho-JNK, phospho-JNK/JNK ratio, and Bcl-2 were significantly elevated in AD subjects. Soluble Aβ1-42 and fibrillar Aβ measured by [(3)H] Pittsburgh compound-B ([(3)H]PiB) binding were significantly higher in AD subjects compared with MCI and NCI subjects. The density of plaques showed a trend to increase, but only 6-CN-PiB-positive plaques reached significance in AD subjects. AT8-positive, TOC-1-positive, and Tau C3-positive NFT densities were unchanged, whereas only AT8-positive neuropil thread density was statistically higher in AD subjects. A negative correlation was found between proNGF, phospho-JNK, and Bcl-2 levels and phospho-JNK/JNK ratio and cognition, whereas proNGF correlated positively with 6-CN-PiB-positive plaques during disease progression.
Data indicate that precuneus neurotrophin pathways are resilient to amyloid toxicity during the onset of AD.
在阿尔茨海默病（AD）中，楔前叶胆碱乙酰转移酶活性降低与更多的β-淀粉样蛋白（Aβ）同时出现。在疾病发作期间，这种胆碱能缺陷是否与神经生长因子（NGF）信号改变及其与Aβ斑块和神经原纤维缠结（NFT）病理的关系尚不清楚。
使用生物化学和组织化学方法，对62名生前诊断为非认知功能障碍（NCI；n = 23）、轻度认知障碍（MCI；n = 21）和轻度至中度AD（n = 18）的受试者，评估楔前叶NGF上游和下游信号水平与Aβ和NFT病理的相关性。
免疫印迹显示AD受试者中前体NGF水平升高，但MCI受试者中未升高，而同源受体未发生变化。各组间下游存活激酶信号蛋白Erk和磷酸化Erk的蛋白水平无显著差异。AD受试者中凋亡性磷酸化JNK、磷酸化JNK/JNK比值和Bcl-2显著升高。与MCI和NCI受试者相比，AD受试者中通过[（3）H]匹兹堡化合物-B（[（3）H]PiB）结合测量的可溶性Aβ1-42和纤维状Aβ显著更高。斑块密度呈增加趋势，但仅6-CN-PiB阳性斑块在AD受试者中具有统计学意义。AT8阳性、TOC-1阳性和Tau C3阳性NFT密度未发生变化，而仅AD受试者中AT8阳性神经毡丝密度在统计学上更高。在前体NGF、磷酸化JNK和Bcl-2水平以及磷酸化JNK/JNK比值与认知之间发现负相关，而在前体NGF与疾病进展期间的6-CN-PiB阳性斑块之间发现正相关。
数据表明，在AD发病期间，楔前叶神经营养因子通路对淀粉样蛋白毒性具有耐受性。
