TY - JOUR
T1 - Hippocampal expression of murine IL-4 results in exacerbation of amyloid deposition
AU - Chakrabarty, Paramita
AU - Tianbai, Li
AU - Herring, Amanda
AU - Ceballos-Diaz, Carolina
AU - Das, Pritam
AU - Golde, Todd E.
N1 - Funding Information:
This work was supported by Mayo Clinic (TEG), National Institutes of Health/ National Institute on Aging Grants (RO1AG18454, RO1AG29886, P01AG25531; TEG) and American Health Assistance Foundation Grant A2009061 (PD).
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Adeno-associated virus
KW - Amyloid plaque
KW - Amyloid precursor protein
KW - Hippocampus
KW - Inflammation
KW - Interleukin 4
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U2 - 10.1186/1750-1326-7-36
DO - 10.1186/1750-1326-7-36
M3 - Article
C2 - 22838967
AN - SCOPUS:84864193530
SN - 1750-1326
VL - 7
JO - Molecular neurodegeneration
JF - Molecular neurodegeneration
IS - 1
M1 - 36
ER -