Loeffler David A, Camp Dianne M, Bennett David A
Neurology Research Laboratory, William Beaumont Hospital Research Institute, Royal Oak, MI 48073, USA.
J Neuroinflammation. 2008 Mar 11;5:9. doi: 10.1186/1742-2094-5-9.
Complement activation is increased in Alzheimer's disease (AD), but its significance is unclear. The objective of this study was to determine the relationship between complement activation and cognition during the development of AD.
iC3b, C9, Bielschowsky, and Gallyas staining was performed on aged normal (n = 17), mild cognitively impaired (n = 12), and AD (n = 17-18) inferior temporal gyrus specimens. Plaques were counted in 10x fields with high numbers of Bielschowsky-stained plaques. One-way ANOVA was used to determine between-group differences for plaque counts and measures of cognitive function, and linear regression was used to evaluate global cognition as a function of Bielschowsky-stained plaques. Terms for iC3b- and C9-stained plaques were then added sequentially as additional predictors in a "mediation analysis" model.
Complement was detected on plaques in all groups, and on neurofibrillary tangles only in AD specimens. iC3b, C9, and Bielschowsky-stained plaque counts increased 2.5- to 3-fold in AD vs. other groups (all p < or = 0.01). C9 staining was present on some diffuse plaques, as well as on neuritic plaques. Bielschowsky-stained and complement-stained plaque counts were highly correlated, and were negatively correlated with cognitive measures. When the Bielschowsky plaque count was used as a predictor, its correlations with cognitive measures were statistically significant, but when iC3b and C9 plaque counts were added as additional predictors, these correlations were no longer significant. This loss of significance was attributed to multicollinearity, i.e., high correlations between Bielschowsky-stained and complement-stained plaque counts.
Both early-stage (iC3b) and late-stage (C9) complement activation occurs on neocortical plaques in subjects across the cognitive spectrum; contrary to previous reports, C9 is present on some diffuse plaques. Because of high correlations between complement-stained and Bielschowsky-stained plaque counts, quantitative assessment of the extent to which complement activation may mediate the relationship between plaques and cognitive function could not be performed. Additional studies with animal models of AD (if late-stage complement activation can be demonstrated), or possibly a trial in AD patients with an inhibitor of late-stage complement activation, may be necessary to determine the significance of this process in AD.
阿尔茨海默病（AD）中补体激活增加，但其意义尚不清楚。本研究的目的是确定AD发展过程中补体激活与认知之间的关系。
对老年正常（n = 17）、轻度认知障碍（n = 12）和AD（n = 17 - 18）患者的颞下回标本进行iC3b、C9、Bielschowsky和Gallyas染色。在10倍视野中对Bielschowsky染色斑块数量较多的区域进行斑块计数。采用单因素方差分析确定斑块计数和认知功能测量的组间差异，并采用线性回归评估Bielschowsky染色斑块数量与整体认知的关系。然后在“中介分析”模型中依次添加iC3b和C9染色斑块数量作为额外预测因子。
所有组的斑块上均检测到补体，仅在AD标本的神经原纤维缠结上检测到补体。与其他组相比，AD组中iC3b、C9和Bielschowsky染色的斑块数量增加了2.5至3倍（所有p≤0.01）。C9染色出现在一些弥漫性斑块以及神经炎斑块上。Bielschowsky染色和补体染色的斑块数量高度相关，且与认知测量呈负相关。当以Bielschowsky斑块数量作为预测因子时，其与认知测量的相关性具有统计学意义，但当添加iC3b和C9斑块数量作为额外预测因子时，这些相关性不再显著。这种显著性的丧失归因于多重共线性，即Bielschowsky染色和补体染色的斑块数量之间高度相关。
在整个认知谱的受试者中，新皮质斑块上均发生早期（iC3b）和晚期（C9）补体激活；与先前报道相反，C9存在于一些弥漫性斑块上。由于补体染色和Bielschowsky染色的斑块数量之间高度相关，无法对补体激活可能介导斑块与认知功能之间关系的程度进行定量评估。可能需要对AD动物模型进行进一步研究（如果能证明晚期补体激活），或者对晚期补体激活抑制剂进行AD患者试验，以确定这一过程在AD中的意义。
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