A beneficial role for IL-1 beta in Alzheimer disease?

Abstract

While the term neuroinflammation often conjures up images of cellular damage, mounting evidence suggests that certain proinflammatory molecules, such as the cytokine IL-1 beta, may have beneficial and protective effects. In a report in this issue of the JCI, Shaftel and coworkers have generated an elegant mouse model in which local hippocampal overexpression of IL-1 beta in an Alzheimer disease (AD) transgenic mouse model resulted not in the expected exacerbation of the amyloid beta plaque deposition common to AD, but instead in plaque amelioration (see the related article beginning on page 1595). Thus, manipulation of the immune system may be a potential therapeutic approach to protect against AD, although further studies are needed to understand all of the downstream effects of this manipulation.

Figure 1. Overexpression of IL-1β activates glial cells and reduces Aβ plaque deposition in a mouse model of AD.

In this issue of the JCI, Shaftel and colleagues (5) used XAT technology to generate IL-1β^XAT transgenic mice and crossbred these mice with APP/PS1 mice, a mouse model used to study AD. Intrahippocampal injection of FIV-Cre at 6 months of age locally activated the IL-1β transgene and increased the levels of IL-1β and glial fibrillary acid protein (GFAP), indicative of astrocytic activation, as well as Iba-1 and MHC class II, indicative of microglial activation. One month later, instead of observing a worsening of AD-like pathogenesis as expected, the authors found that IL-1β overexpression in the APP/PS1+IL-1β mouse resulted in reduced Aβ plaque deposition and lower insoluble Aβ levels in the injected ipsilateral hippocampus compared with the control-injected contralateral hippocampus. Levels of APP and β-secretase, one of the APP-cleaving enzymes responsible for generating Aβ, were unchanged, suggesting that Aβ production was not affected. Instead, IL-1β overexpression led to increased microglial activation and possibly, as the authors hypothesize, clearance of Aβ deposits by microglial phagocytosis. CA, cornu ammonis; DG, dentate gyrus.