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The Journal of Neuroscience, September 1, 2002, 22(17):7380-7388
Lack of Neurodegeneration in Transgenic Mice Overexpressing
Mutant Amyloid Precursor Protein Is Associated with Increased Levels of
Transthyretin and the Activation of Cell Survival Pathways
Thor D.
Stein1 and
Jeffrey A.
Johnson1, 2, 3, 4
1 Neuroscience Training Program,
2 Environmental Toxicology Center, 3 School of
Pharmacy, and 4 Waisman Center, University of Wisconsin,
Madison, Wisconsin 53705
Tg2576 mice overexpress a mutant form of human amyloid precursor
protein with the Swedish mutation (APPSw), resulting
in high  -amyloid (A) 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 APPSw mice were compared with age-matched controls. The expression of transthyretin, a
protein shown to sequester A 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 APPSw 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 APPSw 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 APPSw 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 APPSw mice result from the genetic reprogramming of
neural cells to cope with increased levels of A.
Key words:
Alzheimer's disease; neuroprotection; insulin-like
growth factor; transthyretin; Tg2576; microarray
Copyright © 2002 Society for Neuroscience 0270-6474/02/22177380-09$05.00/0
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