Morris Meaghan, Coste Gabrielle I, Redding-Ochoa Javier, Guo Haidan, Graves Austin R, Troncoso Juan C, Huganir Richard L
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD.
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD.
medRxiv. 2023 Jun 7:2023.02.22.23286323. doi: 10.1101/2023.02.22.23286323.
Primary Age-Related Tauopathy (PART) is characterized by the aggregation of tau in the mesial temporal lobe in older individuals. High pathologic tau stage (Braak stage) or a high burden of hippocampal tau pathology have been associated with cognitive impairment in PART. However, the underlying mechanisms of cognitive impairment in PART are not well understood. Cognitive impairment in many neurodegenerative diseases correlates with synaptic loss, raising the question of whether synaptic loss occurs in PART. To address this, we investigated synaptic changes associated with tau Braak stage and a high tau pathology burden in PART using synaptophysin and phospho-tau immunofluorescence. We compared twelve cases of definite PART with six young controls and six Alzheimer's disease cases. In this study, we identified loss of synaptophysin puncta and intensity in the CA2 region of the hippocampus in cases of PART with either a high stage (Braak IV) or a high burden of neuritic tau pathology. There was also loss of synaptophysin intensity in CA3 associated with a high stage or high burden of tau pathology. Loss of synaptophysin signal was present in AD, but the pattern was distinct from that seen in PART. These novel findings suggest the presence of synaptic loss in PART associated with either a high hippocampal tau burden or a Braak stage IV. These synaptic changes raise the possibility that synaptic loss in PART could contribute to cognitive impairment, though future studies including cognitive assessments are needed to address this question.
原发性年龄相关性tau蛋白病（PART）的特征是tau蛋白在老年人的内侧颞叶聚集。高病理tau蛋白阶段（Braak阶段）或海马tau蛋白病理负担过重与PART中的认知障碍有关。然而，PART中认知障碍的潜在机制尚不清楚。许多神经退行性疾病中的认知障碍与突触丢失相关，这就提出了PART中是否发生突触丢失的问题。为了解决这个问题，我们使用突触素和磷酸化tau蛋白免疫荧光研究了PART中与tau蛋白Braak阶段和高tau蛋白病理负担相关的突触变化。我们将12例确诊的PART患者与6例年轻对照和6例阿尔茨海默病患者进行了比较。在这项研究中，我们发现在高阶段（Braak IV）或神经炎性tau蛋白病理负担过重的PART患者中，海马CA2区的突触素斑点和强度降低。CA3区的突触素强度也因tau蛋白病理的高阶段或高负担而降低。AD患者存在突触素信号缺失，但模式与PART不同。这些新发现表明，在PART中，与高海马tau蛋白负担或Braak IV期相关存在突触丢失。这些突触变化增加了PART中突触丢失可能导致认知障碍的可能性，不过需要包括认知评估在内的未来研究来解决这个问题。
