Selectively Silencing GSK-3 Isoforms Reduces Plaques and Tangles in Mouse Models of Alzheimer's Disease

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.