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Mol Neurodegener. 2012 Jul 29;7:36. doi: 10.1186/1750-1326-7-36.

Hippocampal expression of murine IL-4 results in exacerbation of amyloid deposition.

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  • 1Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, 1275 Center Drive, Gainesville, PO Box #100159, FL 32610, USA.

Abstract

BACKGROUND:

Pro-inflammatory stimuli, including cytokines like Interleukin-1β, Interleukin-6 and Interferon-γ, in the brain have been proposed to exacerbate existing Alzheimer's disease (AD) neuropathology by increasing amyloidogenic processing of APP and promoting further Aβ accumulation in AD. On the other hand, anti-inflammatory cytokines have been suggested to be neuroprotective by reducing neuroinflammation and clearing Aβ. To test this hypothesis, we used adeno-associated virus serotype 1 (AAV2/1) to express an anti-inflammatory cytokine, murine Interleukin-4 (mIL-4), in the hippocampus of APP transgenic TgCRND8 mice with pre-existing plaques.

RESULTS:

mIL-4 expression resulted in establishment of an "M2-like" phenotype in the brain and was accompanied by exacerbated Aβ deposition in TgCRND8 mice brains. No change in holo APP or APP C terminal fragment or phosphorylated tau levels were detected in mIL-4 expressing CRND8 cohorts. Biochemical analysis shows increases in both SDS soluble and insoluble Aβ. mIL-4 treatment attenuates soluble Aβ40 uptake by microglia but does not affect aggregated Aβ42 internalization by microglia or soluble Aβ40 internalization by astrocytes.

CONCLUSIONS:

Short term focal mIL-4 expression in the hippocampus leads to exacerbation of amyloid deposition in vivo, possibly mediated by acute suppression of glial clearance mechanisms. Given that recent preclinical data from independent groups indicate engagement of the innate immune system early on during disease pathogenesis may be beneficial, our present study strongly argues for a cautious re-examination of unwarranted side-effects of anti-inflammatory therapies for neurodegenerative diseases, including AD.

PMID:
22838967
[PubMed - indexed for MEDLINE]
PMCID:
PMC3441281
Free PMC Article
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