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

Abstract

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 α and β isoforms to mechanisms of AD have not been clarified. In this study, we sought to elucidate the role of each GSK-3α and β 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-3α or -β. 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-3α, but not -β reduced SP formation in PDAPP+/− and PS19+/−;PDAPP+/− tg mice. Moreover, both GSK-3α and GSK-3β KD reduced tau phosphorylation and tau misfolding in PS19+/−;PDAPP+/− mice. Next, we generated triple tg mice using the CaMKIIα-Cre (α-calcium/calmodulin-dependent protein kinase II-Cre) system to KD GSK-3α in PDAPP+/− mice for further study the effects of GSK-3α reduction on SP formation. GSK-3α KD showed a significant effect on reducing SPs and ameliorating memory deficits in PDAPP+/− mice. Together, the data from both approaches suggests that GSK-3α contributes to both SP and NFT pathogenesis while GSK-3β only modulates NFT formation, suggesting common but also different targets for both isoforms. These findings highlight the potential importance of GSK-3α as a possible therapeutic target for ameliorating behavioral impairments linked to AD SPs and NFTs.

Inhibition of Glycogen Synthase Kinase-3 Ameliorates β-Amyloid Pathology and Restores Lysosomal Acidification and Mammalian Target of Rapamycin Activity in the Alzheimer Disease Mouse Model

“…It is important to note that L803-mts had a preventative effect, because treatment was begun prior the appearance of A␤ pathology. Our results corroborate previous studies that showed that inhibition in GSK-3 activity reduced A␤ production and/or A␤ pathology (14,16,17). The one study that showed that knock-out of GSK-3␣ or GSK-3␤ in the mouse brain did not affect APP metabolism or A␤ levels (15) was performed using an in vivo model that lacked A␤ pathology, and the role of GSK-3 might have been masked under these conditions.…”

“…80). It should be noted, however, that GSK-3␣ was previously implicated in A␤ production (14) and A␤ plaque formation (17). Thus, it is possible that GSK-3 isozymes influence A␤ pathology by similar and by distinct pathways (14,16,81,82).…”

“…A recent report challenged these results and showed that knock-out of GSK-3␣ or GSK-3␤ in the mouse brain did not alter levels of APP metabolites or A␤ peptides (15). Other studies showed that treatment with GSK-3 inhibitors, lithium, or NP12 or silencing of GSK-3␣ with hairpin RNA constructs reduced A␤ deposition in various AD mouse models (14,16,17), yet our understanding of mechanisms behind GSK-3 regulation of A␤ pathology is limited.…”

An Unbiased Approach to Identifying Tau Kinases That Phosphorylate Tau at Sites Associated with Alzheimer Disease

“…Our screen data suggested that not only is GSK3␤ a good candidate target but that GSK3␣ is also a strong candidate tau kinase as GSK3␣ exhibited the greater magnitude of phosphorylation at all the AD-associated epitopes tested. Moreover, a recent study exploring the specific contributions of each of the GSK3␣ and -␤ isoforms in AD disease progression by using selective viral and gene silencing techniques in transgenic mouse models of AD has been described (21). Their data indicate that GSK3␣ contributes to ).…”

GSK3β, But Not GSK3α, Inhibits the Neuronal Differentiation of Neural Progenitor Cells As a Downstream Target of Mammalian Target of Rapamycin Complex1

“…A recent publication showed that the selective silencing of either GSK3a or GSK3b leads to different consequences in mouse models of Alzheimer's disease [37]. GSK3a-, but not GSK3b-, silenced amyloid precursor protein transgenic mice exhibited reduced levels of amyloid b formation in the adult hippocampus, which indicates the characteristic roles of GSK3a and GSK3b in neurodegenerative disease.…”