1 Department of Neurobiology, Barrow Neurological Institute , Phoenix, Arizona.
2 Center for Dementia Research, Nathan Kline Institute , Orangeburg, New York and NYU Medical Center, New York, New York.
J Neurotrauma. 2018 Jun 1;35(11):1260-1271. doi: 10.1089/neu.2017.5368. Epub 2018 Apr 5.
Military personnel and athletes exposed to traumatic brain injury may develop chronic traumatic encephalopathy (CTE). Brain pathology in CTE includes intracellular accumulation of abnormally phosphorylated tau proteins (p-tau), the main constituent of neurofibrillary tangles (NFTs). Recently, we found that cholinergic basal forebrain (CBF) neurons within the nucleus basalis of Meynert (nbM), which provide the major cholinergic innervation to the cortex, display an increased number of NFTs across the pathological stages of CTE. However, molecular mechanisms underlying nbM neurodegeneration in the context of CTE pathology remain unknown. Here, we assessed the genetic signature of nbM neurons containing the p-tau pretangle maker pS422 from CTE subjects who came to autopsy and received a neuropathological CTE staging assessment (Stages II, III, and IV) using laser capture microdissection and custom-designed microarray analysis. Quantitative analysis revealed dysregulation of key genes in several gene ontology groups between CTE stages. Specifically, downregulation of the nicotinic cholinergic receptor subunit β-2 gene (CHRNB2), monoaminergic enzymes catechol-O-methyltransferase (COMT) and dopa decarboxylase (DDC), chloride channels CLCN4 and CLCN5, scaffolding protein caveolin 1 (CAV1), cortical development/cytoskeleton element lissencephaly 1 (LIS1), and intracellular signaling cascade member adenylate cyclase 3 (ADCY3) was observed in pS422-immunreactive nbM neurons in CTE patients. By contrast, upregulation of calpain 2 (CAPN2) and microtubule-associated protein 2 (MAP2) transcript levels was found in Stage IV CTE patients. These single-population data in vulnerable neurons indicate alterations in gene expression associated with neurotransmission, signal transduction, the cytoskeleton, cell survival/death signaling, and microtubule dynamics, suggesting novel molecular pathways to target for drug discovery in CTE.
创伤性脑损伤（TBI）暴露的军人和运动员可能会发展为慢性创伤性脑病（CTE）。CTE 的脑病理学包括异常磷酸化 tau 蛋白（p-tau）的细胞内积累，其是神经原纤维缠结（NFTs）的主要成分。最近，我们发现梅内特核基底（nbM）内的胆碱能基底前脑（CBF）神经元，其向皮质提供主要的胆碱能支配，在 CTE 的病理阶段表现出 NFT 数量的增加。然而，CTE 病理学背景下 nbM 神经退行性变的分子机制尚不清楚。在这里，我们使用激光捕获显微解剖和定制的微阵列分析，评估了来自接受尸检并接受 CTE 病理分期评估（分期 II、III 和 IV）的 CTE 受试者中含有 p-tau 预缠结标志物 pS422 的 nbM 神经元的遗传特征。定量分析显示，在 CTE 阶段之间，几个基因本体组的关键基因失调。具体而言，在 CTE 患者的 pS422 免疫反应性 nbM 神经元中观察到烟碱型胆碱能受体亚单位β-2 基因（CHRNB2）、单胺能酶儿茶酚-O-甲基转移酶（COMT）和多巴脱羧酶（DDC）、氯离子通道 CLCN4 和 CLCN5、支架蛋白窖蛋白 1（CAV1）、皮质发育/细胞骨架元件无脑回 1（LIS1）和细胞内信号转导级联成员腺苷酸环化酶 3（ADCY3）的下调。相比之下，在 CTE 患者的 IV 期发现钙蛋白酶 2（CAPN2）和微管相关蛋白 2（MAP2）转录水平的上调。这些脆弱神经元的单群体数据表明，与神经递质传递、信号转导、细胞骨架、细胞存活/死亡信号和微管动力学相关的基因表达发生改变，提示 CTE 药物发现的新分子途径。
