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Neuroprotective effects of regulators of the glycogen synthase kinase-3beta signaling pathway in a transgenic model of Alzheimer's disease are associated with reduced amyloid precursor protein phosphorylation


Year of Publication:
Contact PI Name:
Eliezer Masliah
Contact PI Affiliation:
Department of Neurosciences, University of California, San Diego, La Jolla, California, USA
Edward Rockenstein, Magdalena Torrance, Anthony Adame, Michael Mante, Pazit Bar-on, John B. Rose, Leslie Crews
Primary Reference (PubMED ID):
Funding Source:
National Institute of Mental Health (NIMH)
National Institute on Aging (NIA)
Study Goal and Principal Findings:

The glycogen synthase kinase-3beta (GSK3beta) 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 GSK3beta 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 GSK3beta 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 GSK3beta 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 GSK3beta 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-GSK3beta 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 GSK3beta was associated with decreased levels of APP phosphorylation that resulted in decreased amyloid-beta production. In conclusion, the present study showed that modulation of the GSK3beta signaling pathway might also have neuroprotective effects in tg mice by regulating APP maturation and processing and further supports the notion that GSK3beta might be a suitable target for the treatment of AD.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Multi Target

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Morris Water Maze
Hidden Platform Task
Tau Pathology
beta Amyloid Deposits
beta Amyloid Load
Amyloid Precursor Protein (APP) mRNA
Glycogen Synthase Kinase 3 beta (GSK3 beta)
Cytosolic-Glycogen Synthase Kinase 3 beta (GSK3 beta)
Amyloid Precursor Protein (APP)
phospho-Amyloid Precursor Protein (phospho-APP)
Brain-Buffer Soluble beta Amyloid Peptide 42
beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1)
Protein Kinase B (Akt/PKB)
phospho-Protein Kinase B (phospho-Akt/PKB)
Protein Phosphatase 1 (PP1)
phospho-Glycogen Synthase Kinase 3 beta (phospho-GSK3 beta)
Total Tau Protein
Microtubule-Associated Protein 2 (MAP2)
Tau Protein
Brain-beta Amyloid Peptides
Target Engagement (Reduction Glycogen Synthase Kinase 3 beta-Brain)