title: 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 GSK-3β 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 GSK-3β. 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 GSK-3β, 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 of 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 suggest 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.
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, and Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4283, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Hurtado
authors.forename: Laura
authors.initials: L
authors.lastname: Molina-Porcel
authors.forename: Jenna C
authors.initials: JC
authors.lastname: Carroll
authors.forename: Caryn
authors.initials: C
authors.lastname: Macdonald
authors.forename: Awo K
authors.initials: AK
authors.lastname: Aboagye
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D055785:Gene Knockdown Techniques / Q000379:methods; D015316:Genetic Therapy / Q000379:methods / Q000523:psychology*; D038362:Glycogen Synthase Kinase 3 / Q000096:biosynthesis* / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D008569:Memory Disorders / Q000235:genetics / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016875:tau Proteins; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha