Aβ reduction in BACE1 heterozygous null 5XFAD mice is associated with transgenic APP level.
Aβ reduction in BACE1 heterozygous null 5XFAD mice is associated with transgenic APP level.
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DOI：
10.1186/1750-1326-10-1
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发表时间：
2015-01-07
影响因子：
15.1
通讯作者：
Vassar R
中科院分区：
文献类型：
--
作者：
Sadleir KR;Eimer WA;Cole SL;Vassar R
β-分泌酶BACE 1切割APP以启动β-淀粉样肽Aβ的产生，Aβ包括阿尔茨海默病（AD）中的淀粉样斑块。降低BACE 1活性是治疗AD的一种有吸引力的方法，但完全抑制BACE 1可能会产生基于机制的副作用，因为BACE 1 −/−小鼠在轴突导向、髓鞘形成、记忆和其他神经过程中表现出缺陷。由于BACE 1 +/-小鼠表现正常，因此人们有兴趣确定BACE 1减少50%是否可能有效预防或治疗AD。BACE 1杂合子APP转基因小鼠Aβ降低，但降低程度因研究而异。在这里，我们评估了50%BACE1减少对广泛使用的5XFAD小鼠AD模型的影响。BACE 1减少50%可减少雌性5XFAD/BACE 1 +/−小鼠中的Aβ42、斑块和BACE 1裂解的APP片段，但在雄性小鼠中则不然。5XFAD/BACE 1 +/+女性的Aβ42和稳态转基因APP水平高于男性，这可能是由转基因Thy-1启动子中的雌激素反应元件引起的。我们假设雌性5XFAD小鼠中较高的转基因APP水平导致BACE 1不再超过APP，因此50%的BACE 1减少具有显著的Aβ42降低效应。相比之下，5XFAD男性的APP水平较低，即使BACE 1降低50%，BACE 1也会超过APP，从而阻止5XFAD/BACE 1 +/−男性的Aβ42降低。我们还开发并验证了一种使用Aβ42选择性抗体的斑点印迹法，该方法可作为ELISA的准确且经济有效的替代方法，用于测量大脑Aβ42水平。BACE 1减少50%仅降低雌性5XFAD小鼠中的Aβ42，这可能是因为在转基因表达较高的5XFAD雌性小鼠中，BACE 1不超过APP，而在转基因表达较低的5XFAD雄性小鼠中，BACE 1超过APP。我们的研究结果表明，大于50%的BACE 1抑制可能是显着降低Aβ所必需的，因为BACE 1在人脑中可能超过APP。此外，在使用5XFAD小鼠模型或其他Thy-1启动子转基因小鼠的实验中，应使用相同数量的雄性和雌性小鼠，以避免人为的性别相关差异。
The β-secretase, BACE1, cleaves APP to initiate generation of the β-amyloid peptide, Aβ, that comprises amyloid plaques in Alzheimer’s disease (AD). Reducing BACE1 activity is an attractive therapeutic approach to AD, but complete inhibition of BACE1 could have mechanism-based side-effects as BACE1−/− mice show deficits in axon guidance, myelination, memory, and other neurological processes. Since BACE1+/− mice appear normal there is interest in determining whether 50% reduction in BACE1 is potentially effective in preventing or treating AD. APP transgenic mice heterozygous for BACE1 have decreased Aβ but the extent of reduction varies greatly from study to study. Here we assess the effects of 50% BACE1 reduction on the widely used 5XFAD mouse model of AD. 50% BACE1 reduction reduces Aβ42, plaques, and BACE1-cleaved APP fragments in female, but not in male, 5XFAD/BACE1+/− mice. 5XFAD/BACE1+/+ females have higher levels of Aβ42 and steady-state transgenic APP than males, likely caused by an estrogen response element in the transgene Thy-1 promoter. We hypothesize that higher transgenic APP level in female 5XFAD mice causes BACE1 to no longer be in excess over APP so that 50% BACE1 reduction has a significant Aβ42 lowering effect. In contrast, the lower APP level in 5XFAD males allows BACE1 to be in excess over APP even at 50% BACE1 reduction, preventing lowering of Aβ42 in 5XFAD/BACE1+/− males. We also developed and validated a dot blot assay with an Aβ42-selective antibody as an accurate and cost-effective alternative to ELISA for measuring cerebral Aβ42 levels. 50% BACE1 reduction lowers Aβ42 in female 5XFAD mice only, potentially because BACE1 is not in excess over APP in 5XFAD females with higher transgene expression, while BACE1 is in excess over APP in 5XFAD males with lower transgene expression. Our results suggest that greater than 50% BACE1 inhibition might be necessary to significantly lower Aβ, given that BACE1 is likely to be in excess over APP in the human brain. Additionally, in experiments using the 5XFAD mouse model, or other Thy-1 promoter transgenic mice, equal numbers of male and female mice should be used, in order to avoid artifactual gender-related differences.
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5.3
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INGRAHAM, HA;EVANS, GA
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