Abstract
The impact of inflammation suppressor pathways on Alzheimer's disease (AD) evolution remains poorly understood. Human genetic evidence suggests involvement of the cardinal anti-inflammatory cytokine, interleukin-10 (IL10). We crossed the APP/PS1 mouse model of cerebral amyloidosis with a mousedeficient in Il10 (APP/PS1+Il10-/-). Quantitativeinsilico 3D modeling revealed activated Aβ phagocytic microglia in APP/PS1+Il10-/- mice that restricted cerebral amyloidosis. Genome-wide RNA sequencing of APP/PS1+Il10-/- brains showed selective modulation of innate immune genes that drive neuroinflammation. Il10 deficiency preserved synaptic integrity and mitigated cognitive disturbance in APP/PS1 mice. Invitro knockdown of microglial Il10-Stat3 signaling endorsed Aβ phagocytosis, while exogenous IL-10 had the converse effect. Il10 deficiency also partially overcame inhibition of microglial Aβuptake by human Apolipoprotein E. Finally, the IL-10 signaling pathway was abnormally elevated inAD patient brains. Our results suggest that "rebalancing" innate immunity by blocking the IL-10 anti-inflammatory response may be therapeutically relevant for AD.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 534-548 |
| Number of pages | 15 |
| Journal | Neuron |
| Volume | 85 |
| Issue number | 3 |
| DOIs | |
| State | Published - Feb 4 2015 |
Funding
We thank Dr. Serguei Bannykh for human brain sections, Dr. Jean-Philippe Vit for assistance with behavioral testing (Cedars Sinai Medical Center, Los Angeles), Dr. Carol A. Miller from the Alzheimer’s Disease Research Center for frozen human brain tissue (University of Southern California, Los Angeles), and Dr. Eliezer Masliah (University of California, San Diego) for assistance with the synaptophysin immunostaining protocol. We sincerely thank Dr. Tara Weitz (USC Zilkha Neurgenetic Institute, Los Angeles), Drs. Todd Golde, and Paramita Chakrabarty (Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA) and Dr. Pritam Das (Mayo Clinic, Jacksonville) for helpful discussion. We thank Alexander Vesling for technical help with primary microglial cells, and we thank the UCLA Neuroscience Genomics Core (Los Angeles) for assistance with RNAseq. D.G. is supported by an NIH National Research Service Award (1F31NS083339-01A1). This work was supported by the National Institute on Aging (5R00AG029726-04 and 3R00AG029726-04S1, to T.T.), the National Institute on Neurologic Disorders and Stroke (1R01NS076794-01, to T.T.), an Alzheimer’s Association Zenith Fellows Award (ZEN-10-174633, to T.T.), and an American Federation of Aging Research/Ellison Medical Foundation Julie Martin Mid-Career Award in Aging Research (M11472, to T.T.). Finally, we are grateful for startup funds from the Zilkha Neurogenetic Institute, which made this work possible.
ASJC Scopus subject areas
- General Neuroscience
