Abstract
Tg2576 mice overexpress a mutant form of human amyloid precursor protein with the Swedish mutation (APP(Sw)), resulting in high beta-amyloid (Abeta) levels in the brain. Despite this, amyloid plaques do not develop until 12 months of age, and there is no neuronal loss in mice as old as 16 months. Gene expression profiles in the hippocampus and cerebellum of 6-month-old APP(Sw) mice were compared with age-matched controls. The expression of transthyretin, a protein shown to sequester Abeta and prevent amyloid fibril formation in vitro, and several genes in the insulin-signaling pathway, e.g., insulin-like growth factor-2, were increased selectively in the hippocampus of APP(Sw) mice. Concomitant activation of the insulin-like growth factor-1 receptor, Akt, and extracellular signal-regulated protein kinase 1 and 2 as well as increased phosphorylation of Bad also were unique to the hippocampus of APP(Sw) mice. In addition, the increased expression of transthyretin and insulin-like growth factor-2 and the increased phosphorylation of Bad in hippocampal neurons were maintained in 12-month-old APP(Sw) mice when compared with age-matched controls. These results suggest that the slow progression and lack of full-fledged Alzheimer's disease pathology in the hippocampal neurons of APP(Sw) mice result from the genetic reprogramming of neural cells to cope with increased levels of Abeta.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alzheimer Disease / genetics*
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Amyloid Neuropathies / genetics
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Amyloid Neuropathies / metabolism*
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Amyloid Neuropathies / pathology
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Amyloid beta-Protein Precursor / biosynthesis*
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Amyloid beta-Protein Precursor / genetics
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Survival / physiology
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Cerebellum / metabolism
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Disease Progression
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Hippocampus / metabolism
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Hippocampus / pathology
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Humans
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Immunohistochemistry
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Insulin-Like Growth Factor II / genetics
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Insulin-Like Growth Factor II / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism
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Mutation
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Oligonucleotide Array Sequence Analysis
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Phosphorylation
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Prealbumin / genetics
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Prealbumin / metabolism*
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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RNA, Messenger / metabolism
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Receptor, IGF Type 1 / metabolism
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Signal Transduction / physiology*
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bcl-Associated Death Protein
Substances
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Amyloid beta-Protein Precursor
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BAD protein, human
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Bad protein, mouse
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Carrier Proteins
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Prealbumin
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Proto-Oncogene Proteins
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RNA, Messenger
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bcl-Associated Death Protein
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Insulin-Like Growth Factor II
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Receptor, IGF Type 1
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases