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

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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

Fingerprint

Amyloid Plaques
Alzheimer Disease
Tumor Necrosis Factor-alpha
Pathology
Central Nervous System
Receptors, Tumor Necrosis Factor, Type I
Lentivirus
Neuropathology
Inhibition (Psychology)
Amygdala
Amyloid
Hippocampus
Proteins
Cytokines
Inflammation
Neurons
Injections
Antibodies
Brain
Serum

Keywords

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

ASJC Scopus subject areas

  • Neurology

Cite this

McAlpine, F. E., Lee, J. K., Harms, A. S., Ruhn, K. A., Blurton-Jones, M., Hong, J., ... Tansey, M. G. (2009). Inhibition of soluble TNF signaling in a mouse model of Alzheimer's disease prevents pre-plaque amyloid-associated neuropathology. Neurobiology of Disease, 34(1), 163-177. https://doi.org/10.1016/j.nbd.2009.01.006

Inhibition of soluble TNF signaling in a mouse model of Alzheimer's disease prevents pre-plaque amyloid-associated neuropathology. / McAlpine, Fiona E.; Lee, Jae Kyung; Harms, Ashley S.; Ruhn, Kelly A.; Blurton-Jones, Mathew; Hong, John; Das, Pritam; Golde, Todd E.; LaFerla, Frank M.; Oddo, Salvatore; Blesch, Armin; Tansey, Malú G.

In: Neurobiology of Disease, Vol. 34, No. 1, 04.2009, p. 163-177.

Research output: Contribution to journalArticle

McAlpine, FE, Lee, JK, Harms, AS, Ruhn, KA, Blurton-Jones, M, Hong, J, Das, P, Golde, TE, LaFerla, FM, Oddo, S, Blesch, A & Tansey, MG 2009, 'Inhibition of soluble TNF signaling in a mouse model of Alzheimer's disease prevents pre-plaque amyloid-associated neuropathology', Neurobiology of Disease, vol. 34, no. 1, pp. 163-177. https://doi.org/10.1016/j.nbd.2009.01.006
McAlpine, Fiona E. ; Lee, Jae Kyung ; Harms, Ashley S. ; Ruhn, Kelly A. ; Blurton-Jones, Mathew ; Hong, John ; Das, Pritam ; Golde, Todd E. ; LaFerla, Frank M. ; Oddo, Salvatore ; Blesch, Armin ; Tansey, Malú G. / Inhibition of soluble TNF signaling in a mouse model of Alzheimer's disease prevents pre-plaque amyloid-associated neuropathology. In: Neurobiology of Disease. 2009 ; Vol. 34, No. 1. pp. 163-177.
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