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 journalArticle

176 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 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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