Neutralization of transthyretin reverses the neuroprotective effects of secreted amyloid precursor protein (APP) in APPSw mice resulting in tau phosphorylation and loss of hippocampal neurons: Support for the amyloid hypothesis

Thor D. Stein, Nicholas J. Anders, Charles DeCarli, Sic L. Chan, Mark P. Mattson, Jeffrey A. Johnson

Research output: Contribution to journalArticlepeer-review

Abstract

Alzheimer's disease (AD) may be caused by the abnormal processing of the amyloid precursor protein (APP) and the accumulation of β-amyloid (Aβ). The amyloid precursor protein can be proteolytically cleaved into multiple fragments, many of which have distinct biological actions. Although a high level of Aβ can be toxic, the α-secretase cleaved APP (sAPPα) is neuroprotective. However, the mechanism of sAPPα protection is unknown. Here, we show that sAPPα increases the expression levels of several neuroprotective genes and protects organotypic hippocampal cultures from Aβ-induced tau phosphorylation and neuronal death. Antibody interference and small interfering RNA knock-down demonstrate that the sAPPα-driven expression of transthyretin and insulin-like growth factor 2 is necessary for protection against Aβ-induced neuronal death. Mice overexpressing mutant APP possess high levels of sAPPα 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 Aβ, tau phosphorylation, and neuronal loss and apoptosis within the CA1 neuronal field. Therefore, the elevated expression of transthyretin is mediated by sAPPα and protects APP Sw mice from developing many of the neuropathologies observed in AD.

Original languageEnglish (US)
Pages (from-to)7707-7717
Number of pages11
JournalJournal of Neuroscience
Volume24
Issue number35
DOIs
StatePublished - Sep 1 2004
Externally publishedYes

Keywords

  • α-secretase
  • β-amyloid
  • Alzheimer's disease
  • Neurodegeneration
  • Neuropathology
  • Neuroprotection
  • Neurotrophic
  • Organotypic slice culture

ASJC Scopus subject areas

  • Neuroscience(all)

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