Alzheimer disease (AD) is a progressive neurodegenerative disease causing cognitive decline in the aging population. To develop disease-modifying treatments, understanding the mechanisms behind the pathology is important, which should include observations using human brain samples. We reported previously on the association of lysosomal proteins progranulin (PGRN) and prosaposin (PSAP) with amyloid plaques in non-demented aged control and AD brains. In this study, we investigated the possible involvement of PGRN and PSAP in tangle formation using human brain tissue sections of non-demented aged control subjects and AD cases and compared with cases of frontotemporal dementia with granulin (GRN) mutations. The study revealed that decreased amounts of PGRN and PSAP proteins were detected even in immature neurofibrillary tangles, while colocalization was still evident in adjacent neurons in all cases. Results suggest that neuronal loss of PGRN preceded loss of PSAP as tangles developed and matured. The GRN mutation cases exhibited almost complete absence of PGRN in most neurons, while PSAP signal was preserved. Although based on correlative data, we suggest that reduced levels of PGRN and PSAP and their interaction in neurons might predispose to accumulation of p-Tau protein.

中文翻译：

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溶酶体蛋白前粒蛋白和前塞波蛋白的丢失与阿尔茨海默病中神经原纤维缠结的发展增加相关


阿尔茨海默病（AD）是一种进行性神经退行性疾病，导致老年人认知能力下降。为了开发缓解疾病的治疗方法，了解病理学背后的机制很重要，其中应该包括使用人脑样本进行观察。我们之前报道过溶酶体蛋白颗粒体蛋白前体 (PGRN) 和前塞塞蛋白 (PSAP) 与非痴呆老年对照和 AD 大脑中淀粉样斑块的关联。在这项研究中，我们利用非痴呆老年对照受试者和 AD 病例的人脑组织切片，研究了 PGRN 和 PSAP 在缠结形成中的可能参与，并与颗粒蛋白 (GRN) 突变的额颞叶痴呆病例进行了比较。研究表明，即使在未成熟的神经原纤维缠结中，也检测到 PGRN 和 PSAP 蛋白数量减少，而在所有情况下，相邻神经元的共定位仍然很明显。结果表明，随着缠结的发展和成熟，神经元 PGRN 的丢失先于 PSAP 的丢失。 GRN 突变病例表现出大多数神经元几乎完全缺失 PGRN，而 PSAP 信号得以保留。尽管基于相关数据，我们认为 PGRN 和 PSAP 水平降低及其在神经元中的相互作用可能容易导致 p-Tau 蛋白的积累。