| First Author | Hurtado DE | Year | 2012 |
| Journal | J Neurosci | Volume | 32 |
| Issue | 21 | Pages | 7392-402 |
| PubMed ID | 22623685 | Mgi Jnum | J:184975 |
| Mgi Id | MGI:5427024 | Doi | 10.1523/JNEUROSCI.0889-12.2012 |
| Citation | Hurtado DE, et al. (2012) Selectively Silencing GSK-3 Isoforms Reduces Plaques and Tangles in Mouse Models of Alzheimer's Disease. J Neurosci 32(21):7392-402 |
| abstractText | 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-3alpha and GSK-3beta 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-3alpha or GSK-3beta. 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-3alpha, but not GSK-3beta, reduced SP formation in PDAPP(+/-) and PS19(+/-);PDAPP(+/-) tg mice. Moreover, both GSK-3alpha and GSK-3beta KD reduced tau phosphorylation and tau misfolding in PS19(+/-);PDAPP(+/-) mice. Next, we generated triple tg mice using the CaMKIIalpha-Cre (alpha-calcium/calmodulin-dependent protein kinase II-Cre) system to KD GSK-3alpha in PDAPP(+/-) mice for further study of the effects of GSK-3alpha reduction on SP formation. GSK-3alpha KD showed a significant effect on reducing SPs and ameliorating memory deficits in PDAPP(+/-) mice. Together, the data from both approaches suggest that GSK-3alpha contributes to both SP and NFT pathogenesis while GSK-3beta only modulates NFT formation, suggesting common but also different targets for both isoforms. These findings highlight the potential importance of GSK-3alpha as a possible therapeutic target for ameliorating behavioral impairments linked to AD SPs and NFTs. |
