Cognitive Decline in Preclinical Alzheimer's Disease: Amyloid-Beta versus Tauopathy.
Cognitive Decline in Preclinical Alzheimer's Disease: Amyloid-Beta versus Tauopathy.
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DOI：
10.3233/jad-170490
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发表时间：
2018
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影响因子：
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通讯作者：
Mitchell CS
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文献类型：
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作者：
Huber CM;Yee C;May T;Dhanala A;Mitchell CS
我们对51篇同行评议的3xTg-AD小鼠出版物进行了大规模荟萃分析，以比较阿尔茨海默病（AD）定量临床结局指标，包括淀粉样蛋白-β（Aβ），总tau和磷酸化tau（pTau），以及Morris水迷宫（MWM）和新物体识别（NOR）中的认知表现。“高”水平的Aβ（Aβ40，Aβ42）显示出显著但微弱的认知下降趋势（MWM：斜率= 0.336，R2 = 0.149，n = 259，p <0.001; NOR：斜率= 0.156，R2 = 0.064，n = 116，p <0.05）;只有可溶性Aβ或直接测量的Aβ有意义。 3xTg-AD小鼠中的Tau表达在野生型的10-20%内，并且与认知下降无关。相比之下，增加的pTau与MWM（斜率= 0.408，R2 = 0.275，n = 371，p <0.01）和NOR（斜率= 0.319，R2 = 0.176，n = 113，p <0.05）的认知下降直接且显著相关。 虽然检查了多种pTau表位（AT 8、AT 270、AT 180、PHF-1），但AT 8与认知最强相关（斜率= 0.586，R2 = 0.521，n = 185，p < <0.001）。 多元线性回归证实pTau是比Aβ更强的MWM性能预测因子。尽管pTau的物理浓度低于Aβ，但pTau水平与3xTg-AD认知下降更直接和定量相关。pTau在Aβ水平平台期后对神经元缠结的贡献使得pTau即使在晚期临床AD中也是可行的治疗靶标。主成分分析包括激酶（pGSK 3 β、GSK 3 β、CDK 5）诱导的过度磷酸化，将磷酸化ser 9 GSK 3 β确定为MWM变异的主要贡献者。总之，临床前AD认知功能下降的荟萃分析发现tau蛋白病比Aβ更有影响力。尽管如此，复杂的AD相互作用决定了成功的治疗方法可能通过GSK 3途径利用Aβ和pTau之间的协同作用。
We perform a large-scale meta-analysis of 51 peer-reviewed 3xTg-AD mouse publications to compare Alzheimer’s disease (AD) quantitative clinical outcome measures, including amyloid-β (Aβ), total tau, and phosphorylated tau (pTau), with cognitive performance in Morris water maze (MWM) and Novel Object Recognition (NOR). “High” levels of Aβ (Aβ40, Aβ42) showed significant but weak trends with cognitive decline (MWM: slope = 0.336, R2 = 0.149, n = 259, p < 0.001; NOR: slope = 0.156, R2 = 0.064, n = 116, p < 0.05); only soluble Aβ or directly measured Aβ meaningfully contribute. Tau expression in 3xTg-AD mice was within 10–20% of wild type and not associated with cognitive decline. In contrast, increased pTau is directly and significantly correlated with cognitive decline in MWM (slope = 0.408, R2 = 0.275, n = 371, p < < 0.01) and NOR (slope = 0.319, R2 = 0.176, n = 113, p < 0.05). While a variety of pTau epitopes (AT8, AT270, AT180, PHF-1) were examined, AT8 correlated most strongly with cognition (slope = 0.586, R2 = 0.521, n = 185, p < < 0.001). Multiple linear regression confirmed pTau is a stronger predictor of MWM performance than Aβ. Despite pTau’s lower physical concentration than Aβ, pTau levels more directly and quantitatively correlate with 3xTg-AD cognitive decline. pTau’s contribution to neurofibrillary tangles well after Aβ levels plateau makes pTau a viable treatment target even in late-stage clinical AD. Principal component analysis, which included hyperphosphorylation induced by kinases (pGSK3β, GSK3β, CDK5), identified phosphorylated ser9 GSK3β as the primary contributor to MWM variance. In summary, meta-analysis of cognitive decline in preclinical AD finds tauopathy more impactful than Aβ. Nonetheless, complex AD interactions dictate successful therapeutics harness synergy between Aβ and pTau, possibly through the GSK3 pathway.