Selectively Silencing GSK-3 Isoforms Reduces Plaques and Tangles in Mouse Models of Alzheimer's Disease
Selectively Silencing GSK-3 Isoforms Reduces Plaques and Tangles in Mouse Models of Alzheimer's Disease
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DOI：
10.1523/jneurosci.0889-12.2012
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发表时间：
2012-05-23
影响因子：
5.3
通讯作者：
Lee, Virginia M. -Y.
中科院分区：
文献类型：
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作者：
Hurtado, David E.;Molina-Porcel, Laura;Lee, Virginia M. -Y.
糖原合酶激酶 3 (GSK-3) 与阿尔茨海默病 (AD)、老年斑 (SP) 和神经原纤维缠结 (NFT) 的发病机制有关，但 GSK-3 α 和 β 亚型各自对 AD 机制的具体贡献尚未阐明。在这项研究中，我们试图利用新型病毒和遗传学方法阐明 GSK-3 α 和 GSK-3 β 的作用。首先，我们开发了重组腺相关病毒 2/1 短发夹 RNA 构建体，其特异性降低 GSK-3 α 或 GSK-3 β 的表达和活性。这些构建体被注射到 SP (PDAPP (+/-))、SP 和 NFT (PDAPP (+/-);PS19 (+/-)) 或野生型对照的新生儿 AD 转基因 (tg) 小鼠模型中。我们发现，GSK-3 α 的敲低 (KD)（而非 GSK-3 β）可减少 PDAPP (+/-) 和 PS19 (+/-)；PDAPP (+/-) tg 小鼠中 SP 的形成。此外，GSK-3 α 和 GSK-3 β KD 均可减少 PS19 (+/-);PDAPP (+/-) 小鼠中 tau 磷酸化和 tau 错误折叠。接下来，我们使用 CaMKII α-Cre（α-钙/钙调蛋白依赖性蛋白激酶 II-Cre）系统在 PDAPP (+/-) 小鼠中 KD GSK-3 α 生成三重 tg 小鼠，以进一步研究 GSK-3 α 减少对 SP 形成的影响。 GSK-3 α KD 对减少 PDAPP (+/-) 小鼠的 SP 和改善记忆缺陷具有显着效果。总之，两种方法的数据表明，GSK-3 α 有助于 SP 和 NFT 发病机制，而 GSK-3 β 仅调节 NFT 形成，这表明两种亚型有共同但也不同的靶点。这些发现强调了 GSK-3 α 作为改善 AD SP 和 NFT 相关行为障碍的可能治疗靶点的潜在重要性。
Glycogen synthase kinase-3 (GSK-3) is linked to the pathogenesis of Alzheimer's disease (AD), senile plaques (SPs), and neurofibrillary tangles (NFTs), but the specific contributions of each of the GSK-3 alpha and beta isoforms to mechanisms of AD have not been clarified. In this study, we sought to elucidate the role of each GSK-3 alpha and GSK-3 beta using novel viral and genetic approaches. First, we developed recombinant adeno-associated virus 2/1 short hairpin RNA constructs which specifically reduced expression and activity of GSK-3 alpha or GSK-3 beta. These constructs were injected intraventricularly in newborn AD transgenic (tg) mouse models of SPs (PDAPP (+/-)), both SPs and NFTs (PDAPP (+/-);PS19 (+/-)), or wild-type controls. We found that knockdown (KD) of GSK-3 alpha, but not GSK-3 beta, reduced SP formation in PDAPP (+/-) and PS19 (+/-);PDAPP (+/-) tg mice. Moreover, both GSK-3 alpha and GSK-3 beta KD reduced tau phosphorylation and tau misfolding in PS19 (+/-);PDAPP (+/-) mice. Next, we generated triple tg mice using the CaMKII alpha-Cre (alpha-calcium/calmodulin dependent protein kinase II-Cre) system to KD GSK-3 alpha in PDAPP (+/-) mice for further study of the effects of GSK-3 alpha reduction on SP formation. GSK-3 alpha KD showed a significant effect on reducing SPs and ameliorating memory deficits in PDAPP (+/-) mice. Together, the data from both approaches suggest that GSK-3 alpha contributes to both SP and NFT pathogenesis while GSK-3 beta only modulates NFT formation, suggesting common but also different targets for both isoforms. These findings highlight the potential importance of GSK-3 alpha as a possible therapeutic target for ameliorating behavioral impairments linked to AD SPs and NFTs.