Peripheral administration of an anti-TNF-α receptor fusion protein counteracts the amyloid induced elevation of hippocampal TNF-α levels and memory deficits in mice

Neurochem Int. 2014 Jun;72:10-3. doi: 10.1016/j.neuint.2014.04.001. Epub 2014 Apr 13.

Abstract

Alzheimer's disease has long been associated with increased inflammation in the brain. Activated microglia and increased production of the inflammatory cytokines such as TNF-α, have been proposed to contribute to the onset and progression of the disease. We investigated if systemic administration of an anti-tumor necrosis factor (TNF) biologic medication clinically validated for rheumatoid arthritis (RA), TNF receptor 2 fused to a Fc domain (TNFR2:Fc), could ameliorate the behavioral symptoms and decrease neuroinflammation in a non-transgenic mouse model mimicking some hallmarks of the disease. Seven days after a single intracebroventricular (icv) injection of aggregated amyloid beta25-35 (9nmoles), mice displayed significant cognitive deficit in spontaneous alternation (working memory) and inhibitory avoidance (long-term memory) tasks. Alternation percentage decreased from 72.4%±1.3 to chance level (52.6%±1.7); step-through retention latency decreased from 247s to 144s. Subcutaneous administration of 30mg/kg TNFR2:Fc every second day post amyloid beta25-35 icv administration counteracted the amyloid-induced decrease in alternation percentage (66.4s±1.8) and the decreased step-through retention latency (248s±9). Measurement of hippocampal TNF-α levels by ELISA after behavioral assessment showed significant elevation in animals injected with amyloid beta25-35 relative to animals injected with control peptide. In animals treated with 30mg/kg TNFR2:Fc, TNF-α levels in the hippocampus were reduced and were similar to control animals. These data suggest that peripheral administration of TNFR2:Fc counteracts amyloid-induced memory impairment and normalizes increased TNF-α levels in hippocampus of a non-transgenic mouse model of amyloid induced cognitive deficit.

Keywords: Alzheimer disease; Biologics; Neuroinflammation; TNF-α.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / antagonists & inhibitors*
  • Amyloid / toxicity*
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / toxicity
  • Animals
  • Avoidance Learning / drug effects
  • Memory Disorders / chemically induced
  • Memory Disorders / metabolism*
  • Memory Disorders / prevention & control*
  • Memory, Short-Term / drug effects
  • Mice
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / toxicity
  • Psychomotor Performance / drug effects
  • Receptors, Tumor Necrosis Factor / antagonists & inhibitors*
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Recombinant Fusion Proteins / pharmacology
  • TNF Receptor-Associated Factor 2 / genetics
  • TNF Receptor-Associated Factor 2 / pharmacology

Substances

  • Amyloid
  • Amyloid beta-Peptides
  • Peptide Fragments
  • Receptors, Tumor Necrosis Factor
  • Recombinant Fusion Proteins
  • TNF Receptor-Associated Factor 2
  • amyloid beta-protein (25-35)