| First Author | Zhang Y | Year | 2014 |
| Journal | Front Aging Neurosci | Volume | 6 |
| Pages | 123 | PubMed ID | 24987368 |
| Mgi Jnum | J:312060 | Mgi Id | MGI:6782726 |
| Doi | 10.3389/fnagi.2014.00123 | Citation | Zhang Y, et al. (2014) Silencing [Formula: see text] Rescues Tau Pathologies and Memory Deficits through Rescuing PP2A and Inhibiting GSK-3beta Signaling in Human Tau Transgenic Mice. Front Aging Neurosci 6:123 |
| abstractText | Increase of inhibitor-2 of protein phosphatase-2A [Formula: see text] is associated with protein phosphatase-2A (PP2A) inhibition and tau hyperphosphorylation in Alzheimer's disease (AD). Down-regulating [Formula: see text] attenuated amyloidogenesis and improved the cognitive functions in transgenic mice expressing amyloid precursor protein (tg2576). Here, we found that silencing [Formula: see text] by hippocampal infusion of [Formula: see text] down-regulated [Formula: see text] (~45%) with reduction of tau phosphorylation/accumulation, improvement of memory deficits, and dendritic plasticity in 12-month-old human tau transgenic mice. Silencing [Formula: see text] not only restored PP2A activity but also inhibited glycogen synthase kinase-3beta (GSK-3beta) with a significant activation of protein kinase A (PKA) and Akt. In HEK293/tau and N2a/tau cells, silencing [Formula: see text] by [Formula: see text] also significantly reduced tau hyperphosphorylation with restoration of PP2A activity and inhibition of GSK-3beta, demonstrated by the decreased GSK-3beta total protein and mRNA levels, and the increased inhibitory phosphorylation of GSK-3beta at serine-9. Furthermore, activation of PKA but not Akt mediated the inhibition of GSK-3beta by [Formula: see text] silencing. We conclude that targeting [Formula: see text] can improve tau pathologies and memory deficits in human tau transgenic mice, and activation of PKA contributes to GSK-3beta inhibition induced by silencing [Formula: see text]in vitro, suggesting that [Formula: see text] is a promising multiple target of AD. |
