title: 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.
abstract: 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.
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.forename: Magdalena
authors.initials: M
authors.lastname: Torrance
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.forename: Michael
authors.initials: M
authors.lastname: Mante
authors.forename: Pazit
authors.initials: P
authors.lastname: Bar-on
authors.forename: John B
authors.initials: JB
authors.lastname: Rose
authors.forename: Leslie
authors.initials: L
authors.lastname: Crews
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology* / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003712:Dendrites / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D005625:Frontal Lobe / Q000473:pathology; D005799:Genes, Dominant; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D013550:Swimming; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride