Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
The Children's Hospital of Philadelphia, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia.
J Neuropathol Exp Neurol. 2019 Jul 1;78(7):585-594. doi: 10.1093/jnen/nlz039.
In sporadic and dominantly inherited Alzheimer disease (AD), aggregation of both tau and α-synuclein may occur in neurons. Aggregates of either protein occur separately or coexist in the same neuron. It is not known whether the coaggregation of tau and α-synuclein in dominantly inherited AD occurs in association with specific mutations of the APP, PSEN1, or PSEN2 genes. The aim of this study was to provide the first characterization of the neuropathologic phenotype associated with the PSEN1 p.A396T mutation in a man who was clinically diagnosed as having AD, but for whom the PSEN1 mutation was found postmortem. The proband, who was 56 years old when cognitive impairment first manifested, died at 67 years of age. Neuropathologically, 3 proteinopathies were present in the brain. Widespread α-synuclein-immunopositive neuronal inclusions suggested a diagnosis of diffuse Lewy body disease (DLBD), while severe and widespread tau and amyloid-β pathologies confirmed the clinical diagnosis of AD. Immunohistochemistry revealed the coexistence of tau and α-synuclein aggregates in the same neuron. Neuropathologic and molecular studies in brains of carriers of the PSEN1 p.A396T mutation or other PSEN1 or PSEN2 mutations associated with the coexistence of DLBD and AD are needed to clarify whether tau and α-synuclein proteinopathies occur independently or whether a relationship exists between α-synuclein and tau that might explain the mechanisms of coaggregation.
在散发性和显性遗传阿尔茨海默病（AD）中，tau 和 α-突触核蛋白都可能在神经元中聚集。这两种蛋白质的聚集体单独发生或共存于同一神经元中。目前尚不清楚显性遗传 AD 中 tau 和 α-突触核蛋白的共聚集是否与 APP、PSEN1 或 PSEN2 基因的特定突变有关。本研究的目的是首次对与 PSEN1 p.A396T 突变相关的神经病理学表型进行特征描述，该突变患者在临床上被诊断为 AD，但在死后发现了 PSEN1 突变。该先证者在认知障碍首次出现时为 56 岁，67 岁时死亡。神经病理学上，大脑中存在 3 种蛋白病。广泛存在的 α-突触核蛋白免疫阳性神经元包含物提示弥漫性路易体病（DLBD）的诊断，而严重和广泛的 tau 和淀粉样蛋白-β 病理学证实了 AD 的临床诊断。免疫组化显示 tau 和 α-突触核蛋白聚集体在同一神经元中共存。需要对携带 PSEN1 p.A396T 突变或其他与 DLBD 和 AD 共存相关的 PSEN1 或 PSEN2 突变的脑进行神经病理学和分子研究，以阐明 tau 和 α-突触核蛋白蛋白病是否独立发生，或者 α-突触核蛋白和 tau 之间是否存在关系，从而解释共聚集的机制。
