Jiang Juan, Yang Chen, Ai Jia-Qi, Zhang Qi-Lei, Cai Xiao-Lu, Tu Tian, Wan Lily, Wang Xiao-Sheng, Wang Hui, Pan Aihua, Manavis Jim, Gai Wei-Ping, Che Chong, Tu Ewen, Wang Xiao-Ping, Li Zhen-Yan, Yan Xiao-Xin
Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, China.
Department of Neurology, Xiangya Hospital, Changsha, China.
Front Aging Neurosci. 2022 Aug 1;14:926904. doi: 10.3389/fnagi.2022.926904. eCollection 2022.
Extracellular β-amyloid (Aβ) deposition and intraneuronal phosphorylated-tau (pTau) accumulation are the hallmark lesions of Alzheimer's disease (AD). Recently, "sorfra" plaques, named for the extracellular deposition of tilin c-terminal gments, are reported as a new AD-related proteopathy, which develop in the human cerebrum resembling the spatiotemporal trajectory of tauopathy. Here, we identified intraneuronal sortilin aggregation as a change related to the development of granulovacuolar degeneration (GVD), tauopathy, and sorfra plaques in the human hippocampal formation. Intraneuronal sortilin aggregation occurred as cytoplasmic inclusions among the pyramidal neurons, co-labeled by antibodies to the extracellular domain and intracellular C-terminal of sortilin. They existed infrequently in the brains of adults, while their density as quantified in the subiculum/CA1 areas increased in the brains from elderly lacking Aβ/pTau, with pTau (i.e., primary age-related tauopathy, PART cases), and with Aβ/pTau (probably/definitive AD, pAD/AD cases) pathologies. In PART and pAD/AD cases, the intraneuronal sortilin aggregates colocalized partially with various GVD markers including casein kinase 1 delta (Ck1δ) and charged multivesicular body protein 2B (CHMP2B). Single-cell densitometry established an inverse correlation between sortilin immunoreactivity and that of Ck1δ, CHMP2B, p62, and pTau among pyramidal neurons. In pAD/AD cases, the sortilin aggregates were reduced in density as moving from the subiculum to CA subregions, wherein sorfra plaques became fewer and absent. Taken together, we consider intraneuronal sortilin aggregation an aging/stress-related change implicating protein sorting deficit, which can activate protein clearance responses including enhanced phosphorylation and hydrolysis, thereby promoting GVD, sorfra, and Tau pathogenesis, and ultimately, neuronal destruction and death.
细胞外β淀粉样蛋白（Aβ）沉积和神经元内磷酸化tau蛋白（pTau）积累是阿尔茨海默病（AD）的标志性病变。最近，以tilin C末端片段的细胞外沉积命名的“sorfra”斑块被报道为一种新的与AD相关的蛋白病，其在人类大脑中的发展类似于tau蛋白病的时空轨迹。在这里，我们确定神经元内sortilin聚集是一种与人类海马结构中颗粒空泡变性（GVD）、tau蛋白病和sorfra斑块发展相关的变化。神经元内sortilin聚集表现为锥体细胞中的细胞质包涵体，由针对sortilin细胞外结构域和细胞内C末端的抗体共同标记。它们在成年人脑中很少存在，而在缺乏Aβ/pTau的老年人、患有pTau（即原发性年龄相关性tau蛋白病，PART病例）以及患有Aβ/pTau（可能/确诊AD，pAD/AD病例）病理的老年人脑中，在海马下脚/CA1区域量化的其密度增加。在PART和pAD/AD病例中，神经元内sortilin聚集体与包括酪蛋白激酶1δ（Ck1δ）和带电多囊泡体蛋白2B（CHMP2B）在内的各种GVD标记物部分共定位。单细胞密度测定法确定了锥体细胞中sortilin免疫反应性与Ck1δ、CHMP2B、p62和pTau的免疫反应性之间呈负相关。在pAD/AD病例中，sortilin聚集体的密度从海马下脚向CA亚区域移动时降低，其中sorfra斑块变得更少且不存在。综上所述，我们认为神经元内sortilin聚集是一种与衰老/应激相关的变化，暗示蛋白质分选缺陷，这可以激活包括增强磷酸化和水解在内的蛋白质清除反应，从而促进GVD、sorfra和Tau发病机制，最终导致神经元破坏和死亡。
