PMID- 22623685
OWN - NLM
STAT- MEDLINE
DCOM- 20120803
LR  - 20211021
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 32
IP  - 21
DP  - 2012 May 23
TI  - Selectively silencing GSK-3 isoforms reduces plaques and tangles in mouse models 
      of Alzheimer's disease.
PG  - 7392-402
LID - 10.1523/JNEUROSCI.0889-12.2012 [doi]
AB  - 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.
FAU - Hurtado, David E
AU  - Hurtado DE
AD  - 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.
FAU - Molina-Porcel, Laura
AU  - Molina-Porcel L
FAU - Carroll, Jenna C
AU  - Carroll JC
FAU - Macdonald, Caryn
AU  - Macdonald C
FAU - Aboagye, Awo K
AU  - Aboagye AK
FAU - Trojanowski, John Q
AU  - Trojanowski JQ
FAU - Lee, Virginia M-Y
AU  - Lee VM
LA  - eng
GR  - P01 AG017586/AG/NIA NIH HHS/United States
GR  - P01 AG011542/AG/NIA NIH HHS/United States
GR  - T32 GM007229/GM/NIGMS NIH HHS/United States
GR  - AG17586/AG/NIA NIH HHS/United States
GR  - T32-GM07229/GM/NIGMS NIH HHS/United States
GR  - AG11542/AG/NIA NIH HHS/United States
GR  - T32 AG000255/AG/NIA NIH HHS/United States
GR  - T32-AG000255/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (tau Proteins)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - EC 2.7.11.1 (Gsk3b protein, mouse)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
RN  - EC 2.7.11.26 (glycogen synthase kinase 3 alpha)
SB  - IM
MH  - Alzheimer Disease/genetics/metabolism/*pathology
MH  - Animals
MH  - Brain/metabolism/pathology
MH  - Disease Models, Animal
MH  - Female
MH  - Gene Knockdown Techniques/methods
MH  - Genetic Therapy/methods/*psychology
MH  - Glycogen Synthase Kinase 3/*biosynthesis/*physiology
MH  - Glycogen Synthase Kinase 3 beta
MH  - Male
MH  - Memory Disorders/genetics/therapy
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Neurofibrillary Tangles/*metabolism
MH  - Plaque, Amyloid/*metabolism
MH  - Signal Transduction/genetics/physiology
MH  - tau Proteins/metabolism
PMC - PMC3368584
MID - NIHMS379866
EDAT- 2012/05/25 06:00
MHDA- 2012/08/04 06:00
PMCR- 2012/11/23
CRDT- 2012/05/25 06:00
PHST- 2012/05/25 06:00 [entrez]
PHST- 2012/05/25 06:00 [pubmed]
PHST- 2012/08/04 06:00 [medline]
PHST- 2012/11/23 00:00 [pmc-release]
AID - 32/21/7392 [pii]
AID - 3778510 [pii]
AID - 10.1523/JNEUROSCI.0889-12.2012 [doi]
PST - ppublish
SO  - J Neurosci. 2012 May 23;32(21):7392-402. doi: 10.1523/JNEUROSCI.0889-12.2012.