Journal
JOURNAL OF NEUROSCIENCE
Volume 24, Issue 35, Pages 7707-7717Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2211-04.2004
Keywords
Alzheimer's disease; alpha-secretase; neuropathology; neurotrophic; neurodegeneration; neuroprotection; organotypic slice culture; beta-amyloid
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Funding
- NIA NIH HHS [P30 AG10129, P30 AG010129] Funding Source: Medline
- NIEHS NIH HHS [R01 ES008089, R29 ES008089, ES08089, ES10042, R01 ES010042] Funding Source: Medline
- NIGMS NIH HHS [T32 GM008692] Funding Source: Medline
- CSRD VA [I01 CX001038] Funding Source: Medline
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Alzheimer's disease (AD) may be caused by the abnormal processing of the amyloid precursor protein (APP) and the accumulation of beta-amyloid (Abeta). The amyloid precursor protein can be proteolytically cleaved into multiple fragments, many of which have distinct biological actions. Although a high level of Abeta can be toxic, the alpha-secretase cleaved APP (sAPPalpha) is neuroprotective. However, the mechanism of sAPPalpha protection is unknown. Here, we show that sAPPalpha increases the expression levels of several neuroprotective genes and protects organotypic hippocampal cultures from Abeta-induced tau phosphorylation and neuronal death. Antibody interference and small interfering RNA knock-down demonstrate that the sAPPalpha-driven expression of transthyretin and insulin-like growth factor 2 is necessary for protection against Abeta-induced neuronal death. Mice overexpressing mutant APP possess high levels of sAPPalpha 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 Abeta, tau phosphorylation, and neuronal loss and apoptosis within the CA1 neuronal field. Therefore, the elevated expression of transthyretin is mediated by sAPPalpha and protects APP(Sw) mice from developing many of the neuropathologies observed in AD.
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