We recently identified Secernin-1 (SCRN1) as a novel amyloid plaque associated protein using localized proteomics. Immunohistochemistry studies confirmed that SCRN1 was present in plaque-associated dystrophic neurites and also revealed distinct and abundant co-localization with neurofibrillary tangles (NFTs). Little is known about the physiological function of SCRN1 and its role in Alzheimer's disease (AD) and other neurodegenerative diseases has not been studied. Therefore, we performed a comprehensive study of SCRN1 distribution in neurodegenerative diseases. Immunohistochemistry was used to map SCRN1 accumulation throughout the progression of AD in a cohort of 58 patients with a range of NFT pathology (Abundant NFT, n = 21; Moderate NFT, n = 22; Low/No NFT, n = 15), who were clinically diagnosed as having AD, mild cognitive impairment or normal cognition. SCRN1 accumulation was also examined in two cases with both Frontotemporal Lobar Degeneration (FTLD)-Tau and AD-related neuropathology, cases of Down Syndrome (DS) with AD (n = 5), one case of hereditary cerebral hemorrhage with amyloidosis - Dutch type (HCHWA-D) and other non-AD tauopathies including: primary age-related tauopathy (PART, [n = 5]), Corticobasal Degeneration (CBD, [n = 5]), Progressive Supranuclear Palsy (PSP, [n = 5]) and Pick's disease (PiD, [n = 4]). Immunohistochemistry showed that SCRN1 was a neuronal protein that abundantly accumulated in NFTs and plaque-associated dystrophic neurites throughout the progression of AD. Quantification of SCRN1 immunohistochemistry confirmed that SCRN1 preferentially accumulated in NFTs in comparison to surrounding non-tangle containing neurons at both early and late stages of AD. Similar results were observed in DS with AD and PART. However, SCRN1 did not co-localize with phosphorylated tau inclusions in CBD, PSP or PiD. Co-immunoprecipitation revealed that SCRN1 interacted with phosphorylated tau in human AD brain tissue. Together, these results suggest that SCRN1 is uniquely associated with tau pathology in AD, DS and PART. As such, SCRN1 has potential as a novel therapeutic target and could serve as a useful biomarker to distinguish AD from other tauopathies.

中文翻译：

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Secernin-1是一种新型的磷酸化tau结合蛋白，可在阿尔茨海默氏病而非其他疾病中蓄积。

我们最近使用局部蛋白质组学将Secernin-1（SCRN1）确定为一种新型淀粉样蛋白斑块相关蛋白。免疫组织化学研究证实，SCRN1存在于斑块相关的营养不良性神经突中，并且还揭示了与神经原纤维缠结（NFT）的独特且丰富的共定位。关于SCRN1的生理功能及其在阿尔茨海默氏病（AD）和其他神经退行性疾病中的作用知之甚少。因此，我们对神经退行性疾病中SCRN1的分布进行了全面的研究。免疫组化方法用于在58名NFT病理范围广泛的患者（丰富的NFT，n = 21；中度NFT，n = 22；低/无NFT，n = 15）的队列研究中，对整个AD进程中SCRN1的积累进行定位。被临床诊断为患有AD，轻度认知障碍或正常认知。还检查了2例额颞叶大叶变性（FTLD）-Tau和AD相关的神经病理学，1例唐氏综合症（DS）和AD（n = 5），1例患有淀粉样变性的遗传性脑出血-荷兰型（HCHWA-D）和其他非AD的Tauopathies，包括：原发性年龄相关的tauopathy（PART，[n = 5]），皮质基底变性（CBD，[n = 5]），进行性核上性麻痹（PSP，[n = 5] ]）和皮克氏病（PiD，[n = 4]）。免疫组织化学显示，SCRN1是一种神经元蛋白，在整个AD的发展过程中大量积累在NFT和斑块相关的营养不良性神经突中。SCRN1免疫组织化学的定量证实，与AD早期和晚期的周围非缠结神经元相比，SCRN1优先积累在NFT中。在带有AD和PART的DS中观察到了相似的结果。但是，SCRN1并未与CBD，PSP或PiD中的磷酸化tau夹杂物共定位。免疫共沉淀显示SCRN1与人AD脑组织中的磷酸化tau相互作用。总之，这些结果表明，SCRN1与AD，DS和PART中的tau病理学具有独特的关联。因此，SCRN1具有作为新型治疗靶标的潜力，并且可以用作区分AD与其他疾病的有用生物标记。PSP或PiD。免疫共沉淀显示SCRN1与人AD脑组织中的磷酸化tau相互作用。总之，这些结果表明，SCRN1与AD，DS和PART中的tau病理学具有独特的关联。因此，SCRN1具有作为新型治疗靶标的潜力，并且可以用作区分AD与其他疾病的有用生物标记。PSP或PiD。免疫共沉淀显示SCRN1与人AD脑组织中的磷酸化tau相互作用。总之，这些结果表明，SCRN1与AD，DS和PART中的tau病理学具有独特的关联。因此，SCRN1具有作为新型治疗靶标的潜力，并且可以用作区分AD与其他疾病的有用生物标记。