Loss of lysosomal proteins Progranulin and Prosaposin associated with increased neurofibrillary tangle development in Alzheimer’s disease.
Loss of lysosomal proteins Progranulin and Prosaposin associated with increased neurofibrillary tangle development in Alzheimer’s disease.
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溶酶体蛋白颗粒体蛋白前体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有关。
DOI：
10.1093/jnen/nlab056
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Walker DG
中科院分区：
文献类型：
--
作者：
Mendsaikhan A;Tooyama I;Serrano GE;Beach TG;Walker DG
阿尔茨海默病(AD)是一种进行性神经退行性疾病，导致老年人群认知功能下降。为了开发改善疾病的治疗方法，了解病理背后的机制是重要的，这应该包括使用人脑样本进行观察。我们先前报道了溶酶体蛋白原颗粒(PGRN)和原皂苷(PSAP)与非痴呆老年对照组和AD脑中淀粉样斑块的关系。在这项研究中，我们利用非痴呆老年对照组和AD患者的人脑组织切片，研究了PGRN和PSAP在纠缠形成中的可能参与，并与伴有颗粒蛋白(GRN)突变的额颞叶痴呆患者进行了比较。研究表明，即使在未成熟的神经纤维缠结中，也可以检测到PGRN和PSAP蛋白的减少，而所有病例的相邻神经元中仍存在明显的共定位。结果表明，随着缠结的发展和成熟，PGRN神经元的丢失先于PSAP的丢失。在GRN突变的情况下，大多数神经元几乎完全不存在PGRN，而PSAP信号仍被保留。虽然基于相关数据，但我们认为，神经元中PGRN和PSAP水平的降低及其相互作用可能有利于p-Tau蛋白的积聚。
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. TheGRNmutation 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.