Loss of oligodendrocyte‐derived IL‐33 results in increased amyloid plaque deposition in APP/PS1 mice

Abstract

AbstractBackgroundGlial cells in the central nervous system (CNS) express IL‐33, a member of the IL‐1 family. IL‐33 is known to regulate microglial phagocytic activity toward amyloid β. In the aged brain, unlike the young counterpart, IL‐33 is predominantly expressed by oligodendrocytes (OLs), but the role of OL‐derived IL‐33 in Alzheimer’s disease (AD) is unknown.MethodOL‐specific IL‐33 conditional knockout (cKO) mice were further crossed with APPswe/Psen1 dE9 (APP/PS1) and Mobp‐EGFP transgenic mice. Cortical lysates from one‐year‐old male APP/PS1 (n = 15) and APP/PS1 + IL‐33 cKO (n = 16) mice were used for the quantitative analysis (MSD and ELISA) of amyloid β 1‐42 (Aβ1‐42) and Aβ1‐40. Immunofluorescence and morphometric analysis were also performed to measure Aβ‐covered or LAMP1‐covered areas in different regions of the mouse brain. EGFP+ OLs were also quantified.ResultsBoth Aβ1‐42 and Aβ1‐40 levels were significantly increased in the cortex (p<0.0001), and so were Aβ plaque‐covered areas in the cortex, corpus callosum, and hippocampus of APP/PS1 + IL‐33 cKO mice compared with control APP/PS1 (p<0.01). OL‐derived IL‐33 loss also resulted in increased accumulation of LAMP1+ dystrophic neurites (p<0.05). However, cortical EGFP+ OL density was unaltered by IL‐33 cKO.ConclusionOL‐derived IL‐33 may play a regulatory role in Aβ clearance during amyloidogenesis, probably via promoting microglial activity, but not in OL survival in the AD brain. These findings support a novel mechanism of instructive interaction between OLs and microglia in disease‐associated neuroinflammation.