title: 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.
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.
authors.affiliation: UCB S.A., CNS Research, Chemin du Foriest, B-1420 Braine-l'Alleud, Belgium. Electronic address: Eric.Detrait@UCB-Group.com.
authors.forename: E R
authors.initials: ER
authors.lastname: Detrait
authors.affiliation: UCB S.A., CNS Research, Chemin du Foriest, B-1420 Braine-l'Alleud, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Danis
authors.affiliation: UCB S.A., CNS Research, Chemin du Foriest, B-1420 Braine-l'Alleud, Belgium.
authors.forename: Y
authors.initials: Y
authors.lastname: Lamberty
authors.affiliation: UCB S.A., CNS Research, Chemin du Foriest, B-1420 Braine-l'Alleud, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Foerch
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000633:toxicity; D011597:Psychomotor Performance / Q000187:drug effects; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000494:pharmacology
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D047992:TNF Receptor-Associated Factor 2; C074636:amyloid beta-protein (25-35)
keywords: Alzheimer disease; Biologics; Neuroinflammation; TNF-α