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The Journal of Neuroscience, September 1, 2004, 24(35):7707-7717; doi:10.1523/JNEUROSCI.2211-04.2004

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Neurobiology of Disease
Neutralization of Transthyretin Reverses the Neuroprotective Effects of Secreted Amyloid Precursor Protein (APP) in APP_Sw Mice Resulting in Tau Phosphorylation and Loss of Hippocampal Neurons: Support for the Amyloid Hypothesis

Thor D. Stein,¹ Nicholas J. Anders,² Charles DeCarli,⁵ Sic L. Chan,⁶ Mark P. Mattson,⁶ and Jeffrey A. Johnson^1,2,3,4

¹Neuroscience Training Program, ²School of Pharmacy, ³Environmental Toxicology Center, and ⁴Waisman Center, University of Wisconsin, Madison, Wisconsin 53705, ⁵Department of Neurology and Center for Neuroscience, University of California Davis, Sacramento, California 95817, and ⁶Laboratory of Neurosciences, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21224

Alzheimer's disease (AD) may be caused by the abnormal processing of the amyloid precursor protein (APP) and the accumulation of -amyloid (A). The amyloid precursor protein can be proteolytically cleaved into multiple fragments, many of which have distinct biological actions. Although a high level of A can be toxic, the -secretase cleaved APP (sAPP) is neuroprotective. However, the mechanism of sAPP protection is unknown. Here, we show that sAPP increases the expression levels of several neuroprotective genes and protects organotypic hippocampal cultures from A-induced tau phosphorylation and neuronal death. Antibody interference and small interfering RNA knock-down demonstrate that the sAPP-driven expression of transthyretin and insulin-like growth factor 2 is necessary for protection against A-induced neuronal death. Mice overexpressing mutant APP possess high levels of sAPP and transthyretin and do not develop the tau phosphorylation or neuronal loss characteristic of human AD. Chronic infusion of an antibody against transthyretin into the hippocampus of mice overexpressing APP with the Swedish mutation (APP_Sw) leads to increased A, tau phosphorylation, and neuronal loss and apoptosis within the CA1 neuronal field. Therefore, the elevated expression of transthyretin is mediated by sAPP and protects APP_Sw mice from developing many of the neuropathologies observed in AD.

Key words: Alzheimer's disease; -secretase; neuropathology; neurotrophic; neurodegeneration; neuroprotection; organotypic slice culture; -amyloid

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Received June 7, 2004; revised July 16, 2004; accepted July 18, 2004.

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