Two decades of intense research have established neuroinflammation as an integral feature of AD, sparked by initial discoveries of colocalization of MHC class II–immunoreactive microglia with neuritic plaques (8
). Shortly thereafter, the importance of IL-1 signaling to AD pathology was recognized, based on observations in reactive glia surrounding plaques (4
). In the ensuing years neuroinflammation became implicated as a primary contributor to AD pathogenesis based on epidemiologic studies linking chronic nonsteroidal antiinflammatory drug (NSAID) use to reduced AD incidence (22
), and IL-1β was identified as a key instigating factor (24
Previously, assigning a functional role to IL-1β expression in AD relied largely on indirect evidence. This evidence included reported associations between AD pathology and IL-1 expression patterns (25
), disease risk and genetic polymorphisms (26
), and the downstream effects of IL-1β treatment in vitro (28
) and in normal animals (17
). Based on these reports, along with demonstrations of detrimental roles in acute neuroinflammatory settings (2
), we expected that our study would reveal IL-1β–driven exacerbation of AD neuropathology.
Instead, this work provides the first evidence to our knowledge that IL-1β expression may underlie a beneficial neuroinflammatory response in AD. Enhanced IL-1β production is a part of a stereotypical host-defense reaction to a wide range of injuries to the CNS (1
), and its expression is augmented in mouse models of AD (29
) and in response to Aβ peptide exposure (31
). In AD, IL-1β expression may serve as an effective homeostatic mechanism to combat amyloid deposition. This would explain the IL-1β–mediated amelioration of plaque pathology seen in our study (Figure ). This mechanism is further supported by reductions in Aβ load observed following intrahippocampal injections of LPS, a potent inducer of IL-1β synthesis, seen in the Tg2576 and APP/PS1 mouse models of AD (32
). These results indicate that neuroinflammatory processes in AD may at times represent an adaptive response and argue against the indiscriminate use of antiinflammatory therapies in AD. Such treatments may block endogenous mechanisms of plaque clearance, such as those driven by IL-1β expression. This may help explain recent failures of clinical trials using NSAIDs in AD (22
While our results provide strong evidence for a beneficial role of IL-1β expression in APP/PS1 mice, they may not fully reflect the complex role that IL-1β plays in AD pathogenesis. Our study focused on a single time period during the disease course, shortly after plaque pathology is first observed (16
), to facilitate detection of the anticipated IL-1β–mediated exacerbation in plaque pathology. Triggering early, localized IL-1β overexpression mediated a substantial reduction in plaque pathology (Figure ). As described above, our results suggest that IL-1 expression in AD, which is thought to parallel worsening of disease pathology (25
), represents a response to counteract plaque accumulation within the brain parenchyma. Ultimately, this balance may be overwhelmed by ongoing plaque deposition, which would explain the prominence of plaques in late-stage AD. We are currently investigating whether IL-1β overexpression can mediate analogous reductions in plaque pathology at later time points in APP/PS1 mice. Additionally, it has been suggested that IL-1β is capable of triggering a vicious cycle of increased APP expression, Aβ synthesis, and further IL-1β elevation in AD (34
). However, in contrast to previously published studies in human cells (35
), we found no evidence for upregulation of the murine APP gene in our model (Supplemental Figure 2E).
Our findings suggest that microglia are the principal mediators of the beneficial effects of IL-1β overexpression in APP/PS1 mice. Through studies of microglial morphology and MHC class II expression, we showed that IL-1β overexpression was capable of driving phenotypic and immunologic activation of microglia (Figure , A and C). In addition to our present results, previous studies have shown microglial activation to be beneficial in other mouse models of AD (36
). Microglial phagocytosis of plaque has been established in vivo and is thought to be a key mechanism underlying effective Aβ immunotherapy (38
). IL-1β overexpression in the APP/PS1 model resulted in increased overlap of activated microglial nuclei with plaques, which could potentially increase the efficiency of plaque phagocytosis (Figure , A, B, and D). This may be coupled with degradation of plaques by microglia-produced proteases (40
IL-1β–driven enhancement of plaque degradation may be explained by increased seeding of bone marrow–derived microglia in the brain, as evidenced by the amoeboid-shaped perivascular cells coexpressing Iba-1 and MHC class II seen in IL-1βXAT
mice (Figure A). This microglial subpopulation is recruited to sites of Aβ deposition and is thought to be the most effective at restricting plaque formation (31
). Robust MCP-1 upregulation in the hippocampi of APP/PS1+IL-1β mice may serve as a potent chemotactic force for such recruitment (Figure C). Enhanced recruitment of bone marrow–derived microglia may be an important mechanism of the IL-1β–driven reductions in plaque pathology seen in the APP/PS1 mice. However, our results do not eliminate the possibility that other cell populations participate in reductions in amyloid pathology. Future studies using GFP expressing bone marrow chimeras will help establish a functional role for these microglial cells.
This study provides the first description to our knowledge of a mouse model capable of chronic IL-1β overexpression and emphasizes the centrality of IL-1β signaling to inflammatory processes of the brain. We have shown that solitary IL-β overexpression was capable of driving a robust neuroinflammatory response in the mouse hippocampus. We believe that the IL-1βXAT mouse presents an invaluable model system that enables exploration of the functional significance of IL-1β overexpression in a wide range of chronic neuroinflammatory disorders. Moreover, this work provides the first functional characterization to our knowledge of the role of IL-1β–driven neuroinflammation in a mouse model of AD. We have provided evidence that IL-1β–driven neuroinflammation may perform a beneficial, adaptive role in mediating a reduction in AD pathology, perhaps through enhancement of microglial phagocytosis of amyloid plaque.