Hippocampus of Ames dwarf mice is resistant to beta-amyloid-induced tau hyperphosphorylation and changes in apoptosis-regulatory protein levels.
The Ames dwarf mouse has a long lifespan and is characterized by a marked resistance to cellular stress, an event that is implicated in the pathogenesis of many neurodegenerative disorders that are associated with aging, including Alzheimer's disease. However, very little is known on the extent to which the Ames dwarf mouse is protected against Alzheimer's disease. We have developed an organotypic slice system cultured from hippocampi of adult dwarf mice and examined deleterious effects of beta-amyloid (Abeta) peptide, a key pathogenic event in the course of Alzheimer's disease. We present the first evidence that long living Ames mice resist beta-amyloid toxicity. We demonstrate that organotypic slices from adult dwarf mice, but not their normal phenotype counterparts (wild type), are resistant to Abeta25-35-induced hyperphosphorylation of tau protein, reduction in levels of the antiapoptotic protein Bcl-2, increase in levels of the pro-apoptotic protein Bax, and activation of caspase 3. Moreover, incubation of organotypic sections with the GSK-3beta inhibitor SB216763 prevented tau phosphorylation but not alterations in levels of Bcl-2, Bax, and caspase-3. Because the hippocampus is a brain area that is severely affected in Alzheimer's disease, our study proposes that organotypic slices from hippocampi of adult Ames dwarf mice may constitute a model system for understanding endogenous factors that may confer protection against Abeta.
Schrag
Matthew
M
Department of Pharmacology, Physiology and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota 58202, USA.
Sharma
Sunita
S
Brown-Borg
Holly
H
Ghribi
Othman
O
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D019610:Cytoprotection / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D007113:Immunity, Innate / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009410:Nerve Degeneration / Q000378:metabolism* / Q000503:physiopathology; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000187:drug effects / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; C074636:amyloid beta-protein (25-35); D051028:bcl-2-Associated X Protein; D016875:tau Proteins; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3