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Brain. 2017 Mar 1;140(3):826-842. doi: 10.1093/brain/aww330.

Interleukin-2 improves amyloid pathology, synaptic failure and memory in Alzheimer's disease mice.

Author information

1
INSERM U1169/MIRCen CEA 92265 Fontenay aux Roses and Université Paris-Sud, Université Paris Saclay, 91400 Orsay, France.
2
AP-HP, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (i2B), F-75651, Paris, France.
3
Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR-S 959, Immunology-Immunopathology-Immunotherapy, F-75013 Paris, France.
4
Division of Cellular Neurobiology, Zoological Institute, TU Braunschweig, Brunswick, Germany.
5
Helmholtz Centre for Infection Research, AG NIND, Inhoffenstr. 7, 38124 Brunswick, Germany.

Abstract

Interleukin-2 (IL-2)-deficient mice have cytoarchitectural hippocampal modifications and impaired learning and memory ability reminiscent of Alzheimer's disease. IL-2 stimulates regulatory T cells whose role is to control inflammation. As neuroinflammation contributes to neurodegeneration, we investigated IL-2 in Alzheimer's disease. Therefore, we investigated IL-2 levels in hippocampal biopsies of patients with Alzheimer's disease relative to age-matched control individuals. We then treated APP/PS1ΔE9 mice having established Alzheimer's disease with IL-2 for 5 months using single administration of an AAV-IL-2 vector. We first found decreased IL-2 levels in hippocampal biopsies of patients with Alzheimer's disease. In mice, IL-2-induced systemic and brain regulatory T cells expansion and activation. In the hippocampus, IL-2 induced astrocytic activation and recruitment of astrocytes around amyloid plaques, decreased amyloid-β42/40 ratio and amyloid plaque load, improved synaptic plasticity and significantly rescued spine density. Of note, this tissue remodelling was associated with recovery of memory deficits, as assessed in the Morris water maze task. Altogether, our data strongly suggest that IL-2 can alleviate Alzheimer's disease hallmarks in APP/PS1ΔE9 mice with established pathology. Therefore, this should prompt the investigation of low-dose IL-2 in Alzheimer's disease and other neuroinflammatory/neurodegenerative disorders.

KEYWORDS:

AAV; gene therapy; immunomodulation; immunosuppression; neurological diseases

PMID:
28003243
DOI:
10.1093/brain/aww330
[Indexed for MEDLINE]

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