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

Paramita Chakrabarty, Li Tianbai, Amanda Herring, Carolina Ceballos-Diaz, Pritam Das, Todd E. Golde

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

Abstract

Background: Pro-inflammatory stimuli, including cytokines like Interleukin-1?, Interleukin-6 and Interferon-β, in the brain have been proposed to exacerbate existing Alzheimers disease (AD) neuropathology by increasing amyloidogenic processing of APP and promoting further A? accumulation in AD. On the other hand, antiinflammatory 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 sideeffects of anti-inflammatory therapies for neurodegenerative diseases, including AD.

Original languageEnglish (US)
Article number36
JournalMolecular neurodegeneration
Volume7
Issue number1
DOIs
StatePublished - 2012

Keywords

  • Adeno-associated virus
  • Amyloid plaque
  • Amyloid precursor protein
  • Hippocampus
  • Inflammation
  • Interleukin 4

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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