SMOC1 has emerged as one of the most significant and consistent new biomarkers of early Alzheimer’s disease (AD). Recent studies show that SMOC1 is one of the earliest changing proteins in AD, with levels in the cerebrospinal fluid increasing many years before symptom onset. Despite this clear association with disease, little is known about the role of SMOC1 in AD or its function in the brain. Therefore, the aim of this study was to examine the distribution of SMOC1 in human AD brain tissue and to determine if SMOC1 influenced amyloid beta (Aβ) aggregation. The distribution of SMOC1 in human brain tissue was assessed in 3 brain regions (temporal cortex, hippocampus, and frontal cortex) using immunohistochemistry in a cohort of 73 cases encompassing advanced AD, mild cognitive impairment (MCI), preclinical AD, and cognitively normal controls. The Aβ- and phosphorylated tau-interaction with SMOC1 was assessed in control, MCI, and advanced AD human brain tissue using co-immunoprecipitation, and the influence of SMOC1 on Aβ aggregation kinetics was assessed using Thioflavin-T assays and electron microscopy. SMOC1 strongly colocalized with a subpopulation of amyloid plaques in AD (43.8 ± 2.4%), MCI (32.8 ± 5.4%), and preclinical AD (28.3 ± 6.4%). SMOC1 levels in the brain strongly correlated with plaque load, irrespective of disease stage. SMOC1 also colocalized with a subpopulation of phosphorylated tau aggregates in AD (9.6 ± 2.6%). Co-immunoprecipitation studies showed that SMOC1 strongly interacted with Aβ in human MCI and AD brain tissue and with phosphorylated tau in human AD brain tissue. Thioflavin-T aggregation assays showed that SMOC1 significantly delayed Aβ aggregation in a dose-dependent manner, and electron microscopy confirmed that the Aβ fibrils generated in the presence of SMOC1 had an altered morphology. Overall, our results emphasize the importance of SMOC1 in the onset and progression of AD and suggest that SMOC1 may influence pathology development in AD.

SMOC1 已成为早期阿尔茨海默病 （AD） 最重要和一致的新生物标志物之一。最近的研究表明，SMOC1 是 AD 中最早变化的蛋白质之一，脑脊液中的水平在症状出现前许多年就已经升高。尽管与疾病有明显的关联，但人们对 SMOC1 在 AD 中的作用或其在大脑中的功能知之甚少。因此，本研究的目的是检查 SMOC1 在人 AD 脑组织中的分布，并确定 SMOC1 是否影响淀粉样蛋白 β （Aβ） 聚集。使用免疫组织化学在 3 个脑区（颞叶皮层、海马和额叶皮层）中评估 SMOC1 在人脑组织中的分布，队列包括 73 例病例，包括晚期 AD 、轻度认知障碍 （MCI）、临床前 AD 和认知正常对照。使用免疫共沉淀在对照、MCI 和晚期 AD 人脑组织中评估 Aβ 和磷酸化 tau 与 SMOC1 的相互作用，并使用硫黄素-T 测定和电子显微镜评估 SMOC1 对 Aβ 聚集动力学的影响。SMOC1 与 AD （43.8 ± 2.4%） 、MCI （32.8 ± 5.4%） 和临床前 AD （28.3 ± 6.4%） 中的淀粉样斑块亚群强烈共定位。大脑中的 SMOC1 水平与斑块负荷密切相关，与疾病阶段无关。SMOC1 还与 AD 中磷酸化 tau 聚集体的亚群共定位 （9.6 ± 2.6%）。免疫共沉淀研究表明，SMOC1 与人 MCI 和 AD 脑组织中的 Aβ 以及人 AD 脑组织中的磷酸化 tau 强烈相互作用。 硫黄素-T 聚集测定显示 SMOC1 以剂量依赖性方式显着延迟 Aβ 聚集，电子显微镜证实在 SMOC1 存在下产生的 Aβ 原纤维具有改变的形态。总体而言，我们的结果强调了 SMOC1 在 AD 发生和发展中的重要性，并表明 SMOC1 可能影响 AD 的病理发展。