BRI2 (ITM2b) inhibits Aβ deposition in vivo
BRI2 (ITM2b) inhibits Aβ deposition in vivo
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DOI：
10.1523/jneurosci.0891-08.2008
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发表时间：
2008-06-04
影响因子：
5.3
通讯作者：
Golde, Todd E.
中科院分区：
文献类型：
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作者：
Kim, Jungsu;Miller, Victor M.;Golde, Todd E.
对 BRI2 (ITM2b) 和淀粉样β前体蛋白 (APP) 基因突变的生物学效应的分析支持了以下假设：英国家族性痴呆和丹麦家族性痴呆和阿尔茨海默氏病 (AD) 中淀粉样肽的脑积聚与神经退行性疾病相关。我们使用体细胞脑转基因技术在 APP 小鼠模型中表达 BRI2 和 BRI2-A beta 1-40 转基因。 BRI2-A beta 1-40 的表达模拟了先前使用传统转基因方法观察到的抑制效果，进一步验证了体脑转基因方法。出乎意料的是，我们还发现野生型人 BRI2 的表达减少了 AD 小鼠模型中的大脑 Aβ 沉积。其他数据表明，BRI2 通过正常加工释放的 23 个氨基酸肽 Bri23 存在于人脑脊液中，在体外抑制 Aβ 聚集，并在体内介导其抗淀粉样蛋白生成作用。这些研究表明 BRI2 是体内 Aβ 沉积的新型介质。
Analyses of the biologic effects of mutations in the BRI2 (ITM2b) and the amyloid beta precursor protein (APP) genes support the hypothesis that cerebral accumulation of amyloidogenic peptides in familial British and familial Danish dementias and Alzheimer's disease (AD) is associated with neurodegeneration. We have used somatic brain transgenic technology to express the BRI2 and BRI2-A beta 1-40 transgenes in APP mouse models. Expression of BRI2-A beta 1-40 mimics the suppressive effect previously observed using conventional transgenic methods, further validating the somatic brain transgenic methodology. Unexpectedly, we also find that expression of wild-type human BRI2 reduces cerebral A beta deposition in an AD mouse model. Additional data indicate that the 23 aa peptide, Bri23, released from BRI2 by normal processing, is present in human CSF, inhibits A beta aggregation in vitro and mediates its anti-amyloidogenic effect in vivo. These studies demonstrate that BRI2 is a novel mediator of A beta deposition in vivo.