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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.

journal_name

Neurochem Int

journal_title

Neurochemistry international

authors

Detrait ER,Danis B,Lamberty Y,Foerch P

doi

10.1016/j.neuint.2014.04.001

subject

Has Abstract

pub_date

2014-06-01 00:00:00

pages

10-3

eissn

0197-0186

issn

1872-9754

pii

S0197-0186(14)00086-2

journal_volume

pub_type

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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.