The glycogen synthase kinase-3β (GSK3β) pathway plays an important role in mediating neuronal fate and synaptic plasticity. In Alzheimer's disease (AD), abnormal activation of this pathway might play an important role in neurodegeneration, and compounds such as lithium that modulate GSK3β activity have been shown to reduce amyloid production and tau phosphorylation in amyloid precursor protein (APP) transgenic (tg) mice. However, it is unclear whether regulation of GSK3β is neuroprotective in APP tg mice. In this context, the main objective of the present study was to determine whether pharmacological or genetic manipulations that block the GSK3β pathway might ameliorate the neurodegenerative alterations in APP tg mice and to better understand the mechanisms involved. For this purpose, two sets of experiments were performed. First, tg mice expressing mutant human APP under the Thy1 promoter (hAPP tg) were treated with either lithium chloride or saline alone. Second, hAPP tg mice were crossed with GSK3β tg mice, in which overexpression of this signaling molecule results in a dominant-negative (DN) effect with inhibition of activity. hAPP tg mice that were treated with lithium or that were crossed with DN–GSK3β tg mice displayed improved performance in the water maze, preservation of the dendritic structure in the frontal cortex and hippocampus, and decreased tau phosphorylation. Moreover, reduced activation of GSK3β was associated with decreased levels of APP phosphorylation that resulted in decreased amyloid-β production. In conclusion, the present study showed that modulation of the GSK3β signaling pathway might also have neuroprotective effects in tg mice by regulating APP maturation and processing and further supports the notion that GSK3β might be a suitable target for the treatment of AD.
Neuroprotective Effects of Regulators of the Glycogen Synthase Kinase-3β Signaling Pathway in a Transgenic Model of Alzheimer's Disease Are Associated with Reduced Amyloid Precursor Protein Phosphorylation
E. Rockenstein,Magdalena Torrance,A. Adame,M. Mante,P. Bar-on,John B. Rose,Leslie A. Crews,E. Masliah
Published 2007 in Journal of Neuroscience
ABSTRACT
PUBLICATION RECORD
- Publication year
2007
- Venue
Journal of Neuroscience
- Publication date
2007-02-21
- Fields of study
Biology, Medicine, Chemistry
- Identifiers
- External record
- Source metadata
Semantic Scholar, PubMed
CITATION MAP
EXTRACTION MAP
CLAIMS
CONCEPTS
- amyloid-β production
The generation of amyloid-β peptides from APP processing in the transgenic mouse model.
Aliases: Aβ production, amyloid beta production
- app phosphorylation
The phosphorylation state of amyloid precursor protein involved in its maturation and processing.
Aliases: amyloid precursor protein phosphorylation, phosphorylated APP
- dendritic structure
The morphology and integrity of dendritic arbors in the frontal cortex and hippocampus.
Aliases: dendritic morphology, dendritic arbor
- dn-gsk3β transgenic mice
Transgenic mice overexpressing a dominant-negative form of GSK3β that inhibits GSK3β activity.
Aliases: dominant-negative GSK3β transgenic mice, GSK3β tg mice
- gsk3β signaling pathway
A signaling cascade centered on glycogen synthase kinase-3β that was manipulated in the mouse model to study neuronal and amyloid-related effects.
Aliases: GSK3β pathway, glycogen synthase kinase-3β signaling pathway
- happ transgenic mice
Transgenic mice expressing mutant human amyloid precursor protein under the Thy1 promoter.
Aliases: hAPP tg mice, APP tg mice
- lithium chloride
A lithium salt used as the pharmacological treatment to modulate GSK3β activity in hAPP transgenic mice.
Aliases: lithium
- tau phosphorylation
The phosphorylation state of tau protein measured as a neurodegeneration-related marker in the mouse brain.
Aliases: phosphorylated tau
- water maze
A spatial navigation task used here to assess learning and memory performance in the mice.
Aliases: Morris water maze
REFERENCES
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