Inhibition of soluble TNF signaling in a mouse model of Alzheimer's disease prevents pre-plaque amyloid-associated neuropathology

Fiona E. McAlpine, Jae Kyung Lee, Ashley S. Harms, Kelly A. Ruhn, Mathew Blurton-Jones, John Hong, Pritam Das, Todd E. Golde, Frank M. LaFerla, Salvatore Oddo, Armin Blesch, Malú G. Tansey

Research output: Contribution to journalArticlepeer-review

179 Scopus citations

Abstract

Microglial activation and overproduction of inflammatory mediators in the central nervous system (CNS) have been implicated in Alzheimer's disease (AD). Elevated levels of the pro-inflammatory cytokine tumor necrosis factor (TNF) have been reported in serum and post-mortem brains of patients with AD, but its role in progression of AD is unclear. Using novel engineered dominant negative TNF inhibitors (DN-TNFs) selective for soluble TNF (solTNF), we investigated whether blocking TNF signaling with chronic infusion of the recombinant DN-TNF XENP345 or a single injection of a lentivirus encoding DN-TNF prevented the acceleration of AD-like pathology induced by chronic systemic inflammation in 3xTgAD mice. We found that chronic inhibition of solTNF signaling with either approach decreased the LPS-induced accumulation of 6E10-immunoreactive protein in hippocampus, cortex, and amygdala. Immunohistological and biochemical approaches using a C-terminal APP antibody indicated that a major fraction of the accumulated protein was likely to be C-terminal APP fragments (β-CTF) while a minor fraction consisted of Aβ40 and 42. Genetic inactivation of TNFR1-mediated TNF signaling in 3xTgAD mice yielded similar results. Taken together, our studies indicate that soluble TNF is a critical mediator of the effects of neuroinflammation on early (pre-plaque) pathology in 3xTgAD mice. Targeted inhibition of solTNF in the CNS may slow the appearance of amyloid-associated pathology, cognitive deficits, and potentially the progressive loss of neurons in AD.

Original languageEnglish (US)
Pages (from-to)163-177
Number of pages15
JournalNeurobiology of Disease
Volume34
Issue number1
DOIs
StatePublished - Apr 1 2009

Keywords

  • 3xTgAD
  • Alzheimer's disease
  • Amyloid precursor protein
  • Amyloid-β
  • Lentivirus
  • Neuroinflammation
  • Tumor necrosis factor
  • β-CTF

ASJC Scopus subject areas

  • Neurology

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