Accelerated Aβ deposition in APPswe/PS1ΔE9 mice with hemizygous deletions of TTR (transthyretin)
Accelerated Aβ deposition in APPswe/PS1ΔE9 mice with hemizygous deletions of TTR (transthyretin)
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DOI：
10.1523/jneurosci.1919-07.2007
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发表时间：
2007-06-27
影响因子：
5.3
通讯作者：
Sisodia, Sangram S.
中科院分区：
文献类型：
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作者：
Choi, Se Hoon;Leight, Susan N.;Sisodia, Sangram S.
阿尔茨海默病（AD）的主要病理损害是淀粉样蛋白β（A β）在脑中的沉积。我们以前报道过，将携带APPswe/PS1 Delta E9转基因的转基因小鼠暴露于富集环境导致A β肽和沉积水平降低，这一发现与编码甲状腺素运载蛋白（TTR）的TTR表达增加相关。TTR在脉络丛中以高水平表达，并且已知结合A β肽并在体外和体内调节它们的聚集。为了探索TTR表达对体内A β水平和沉积的影响，我们将ceAPPswe/PS1 Delta E9转基因小鼠与TTR基因消除的小鼠杂交。我们现在报告，与年龄匹配的ceAPPswe/PS1 Delta E9/TTR+/ +小鼠相比，ceAPPswe/PS1 Delta E9/TTR+/-小鼠脑中A β和沉积的洗涤剂可溶性和甲酸可溶性水平升高。此外，在ceAPPswe/PS1 Delta E9/TTR+/-小鼠的海马和皮质中，A β沉积显著加速。我们的研究结果强烈表明，TTR在体内调节A β沉积中起着关键作用。
A cardinal pathological lesion of Alzheimer's disease (AD) is the deposition of amyloid beta(A beta) in the brain. We previously reported that exposing transgenic mice harboring APPswe/PS1 Delta E9 transgenes to an enriched environment resulted in reduced levels of A beta peptides and deposition, findings that were correlated with an increase in the expression of TTR, encoding transthyretin (TTR). TTR is expressed at high levels in the choroid plexus and known to bind A beta peptides and modulate their aggregation in vitro and in vivo. To explore the impact of TTR expression on A beta levels and deposition in vivo, we crossed ceAPPswe/PS1 Delta E9 transgenic mice to mice with genetic ablations of TTR. We now report that the levels of detergent-soluble and formic acid-soluble levels of A beta and deposition are elevated in the brains of ceAPPswe/PS1 Delta E9/TTR+/- mice compared with age-matched ceAPPswe/PS1 Delta E9/TTR+/ + mice. Moreover, A beta deposition is significantly accelerated in the hippocampus and cortex of ceAPPswe/PS1 Delta E9/TTR+/- mice. Our results strongly suggest that TTR plays a critical role in modulating A beta deposition in vivo.