Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK.
Cognitive Ageing and Impairment Neurosciences, School of Psychology, Social Work and Social Policy, University of South Australia, Adelaide, Australia.
J Alzheimers Dis. 2020;75(1):337-350. doi: 10.3233/JAD-191093.
Pathologies associated with the Tar-DNA binding protein 43 KDa (TDP-43) are associated with neurodegenerative diseases and aging. Phosphorylation of cellular proteins is a well-accepted mechanism of biological control and can be associated with disease pathways. Phosphorylation state associated with TDP-43 associated pathology has not been investigated with respect to dementia status in a population representative sample. TDP-43 immunohistochemistry directed toward phosphorylated (TDP-43P) and unphosphorylated (TDP-43U) was assessed in sections of hippocampus and temporal cortex from 222 brains donated to the population representative Cambridge City over-75s Cohort. Relationships between dementia status and age at death for TDP-43 immunoreactive pathologies by phosphorylation state were investigated. TDP-43 pathologies are common in the oldest old in the population and often do not conform to MacKenzie classification. Increasing age is associated with glial (TDP-43P) and neuronal inclusions (TDP-43P and TDP-43U), neurites, and granulovacuolar degeneration (GVD). Dementia status is associated with GVD and glial (TDP-43 P) and neural inclusions (TDP-43 P and U). Dementia severity was associated with glial (TDP-43P) and neuronal inclusions (TDP-43U and TDP-43P), GVD, and neurites. The associations between dementia severity and both glial cytoplasmic inclusions and GVD were independent from other pathologies and TDP-43 neuronal cytoplasmic inclusions. TDP-43 pathology contributes to dementia status and progression in a variety of ways in different phosphorylation states involving both neurons and glia, independently from age and from classic Alzheimer-related pathologies. TDP-43 pathologies as cytoplasmic inclusions in neurons or glia or as GVD contribute independently to dementia.
与 Tar-DNA 结合蛋白 43 kDa（TDP-43）相关的病理学与神经退行性疾病和衰老有关。细胞蛋白的磷酸化是一种被广泛接受的生物调控机制，可能与疾病途径有关。TDP-43 相关病理学的磷酸化状态尚未在具有代表性的人群样本中针对痴呆状态进行研究。在 222 个捐赠给人群代表性剑桥市 75 岁以上队列的大脑的海马体和颞叶皮层切片中，评估了针对磷酸化（TDP-43P）和未磷酸化（TDP-43U）的 TDP-43 免疫组织化学。通过磷酸化状态研究了 TDP-43 免疫反应性病理学与痴呆状态和死亡年龄之间的关系。TDP-43 病理学在人群中最年长的人中很常见，并且通常不符合 MacKenzie 分类。年龄的增长与神经胶质（TDP-43P）和神经元包含物（TDP-43P 和 TDP-43U）、神经突和颗粒空泡变性（GVD）有关。痴呆状态与 GVD 和神经胶质（TDP-43P）和神经元包含物（TDP-43P 和 U）有关。痴呆严重程度与神经胶质（TDP-43P）和神经元包含物（TDP-43U 和 TDP-43P）、GVD 和神经突有关。痴呆严重程度与神经胶质细胞质包含物和 GVD 之间的关联独立于其他病理学和 TDP-43 神经元细胞质包含物。TDP-43 病理学以各种磷酸化状态参与神经元和神经胶质的不同方式导致痴呆状态和进展，独立于年龄和经典的与阿尔茨海默病相关的病理学。TDP-43 病理学作为神经元或神经胶质中的细胞质包含物或作为 GVD 独立于痴呆。
