Table_1_Corpora amylacea negatively correlate with hippocampal tau pathology in Alzheimer’s disease.DOCX

IntroductionSeverity and distribution of aggregated tau and neurofibrillary tangles (NFT) are strongly correlated with the clinical presentation of Alzheimer’s disease (AD). Clearance of aggregated tau could decrease the rate of NFT formation and delay AD onset. Recent studies implicate corpora amylacea (CA) as a regulator of onset or accumulation of tau pathology. Normally, CA clear brain waste products by amassing cellular debris, which are then extruded into the cerebrospinal fluid to be phagocytosed. The proper functioning of CA may slow progression of AD-associated NFT pathology, and this relationship may be influenced by amount and distribution of phospho-tau (pTau) produced, age, sex, and genetic risk.
ObjectiveThe goal of this study was to determine if CA size and number are associated with hippocampal location and local pTau severity while accounting for variations in age, sex, and genetic risk.
MethodsPostmortem brain hippocampal tissue sections from 40 AD and 38 unaffected donors were immunohistochemically stained with AT8 (pTau) and counter stained with periodic acid Schiff (PAS). Stained sections of the CA1 and CA3 regions of the hippocampus were analyzed. The percent area occupied (%AO) of CA, pTau, and NFT was calculated. Pairwise comparisons and regression modeling were used to analyze the influence of age, pTau %AO, and genetic risk on %AO by CA in each region, separately in donors with AD and unaffected donors.
ResultsCA %AO was significantly higher in the CA3 region compared to CA1 in both groups. A significant negative correlation of CA %AO with both pTau %AO and neurofibrillary tangle %AO in the CA3 region of AD brain donors was found. Regression analysis in the CA3 region revealed a significant negative association between CA with both pTau and age.
ConclusionWe found an increase of CA in the CA3 region, compared to CA1 region, in AD and unaffected donors. This may suggest that the CA3 region is a hub for waste removal. Additionally, the negative correlation between %AO by CA and NFT in the CA3 region of the hippocampus in donors with AD suggests CA could play a role in AD pathologic progression by influencing tau clearance.

引言
聚集型tau蛋白与神经原纤维缠结（neurofibrillary tangles, NFT）的严重程度及分布与阿尔茨海默病（Alzheimer’s disease, AD）的临床表现密切相关。清除聚集型tau蛋白可降低NFT形成速率，延缓AD发病。近期研究表明，淀粉样小体（corpora amylacea, CA）可调控tau病理的发生或积累。正常情况下，淀粉样小体通过收集细胞碎片清除脑内代谢废物，随后将其排入脑脊液以被吞噬细胞吞噬。淀粉样小体的正常功能或许可减缓AD相关NFT病理的进展，而这一作用可能受所产生的磷酸化tau（phospho-tau, pTau）的数量与分布、年龄、性别以及遗传风险的影响。
研究目的
本研究旨在探讨在控制年龄、性别与遗传风险变量的前提下，淀粉样小体的大小与数量是否与海马体的脑区位置以及局部pTau的严重程度相关。
研究方法
本研究选取40名阿尔茨海默病患者与38名健康对照者的死后海马脑组织切片，采用靶向磷酸化tau的AT8抗体进行免疫组织化学染色，并以高碘酸-希夫（periodic acid Schiff, PAS）染色进行复染。对海马CA1与CA3脑区的染色切片进行分析，计算淀粉样小体、pTau以及NFT的面积占比（%AO）。分别在阿尔茨海默病患者与健康对照者群体中，采用两两比较与回归建模分析年龄、pTau面积占比以及遗传风险对各脑区内淀粉样小体面积占比的影响。
研究结果
在两组受试者中，CA3脑区的淀粉样小体面积占比均显著高于CA1脑区。在阿尔茨海默病患者的海马CA3脑区中，淀粉样小体面积占比与pTau面积占比、NFT面积占比均呈显著负相关。对CA3脑区的回归分析显示，淀粉样小体与pTau、年龄均呈显著负相关。
研究结论
本研究发现，无论阿尔茨海默病患者还是健康对照者，其海马CA3脑区的淀粉样小体数量均多于CA1脑区，这提示CA3脑区可能是脑内废物清除的枢纽。此外，阿尔茨海默病患者海马CA3脑区内的淀粉样小体面积占比与NFT面积占比呈负相关，表明淀粉样小体或可通过调控tau蛋白清除过程，参与阿尔茨海默病的病理进展。