Neuroinflammation is a conspicuous feature of Alzheimer disease (AD) pathology and is thought to contribute to the ultimate neurodegeneration that ensues. IL-1 beta has emerged as a prime candidate underlying this response. Here we describe a transgenic mouse model of sustained IL-1 beta overexpression that was capable of driving robust neuroinflammation lasting months after transgene activation. This response was characterized by astrocytic and microglial activation in addition to induction of proinflammatory cytokines. Surprisingly, when triggered in the hippocampus of the APPswe/PS1dE9 mouse model of AD, 4 weeks of IL-1 beta overexpression led to a reduction in amyloid pathology. Congophilic plaque area fraction and frequency as well as insoluble amyloid beta 40 (A beta 40) and A beta 42 decreased significantly. These results demonstrate a possible adaptive role for IL-1 beta-driven neuroinflammation in AD and may help explain recent failures of antiinflammatory therapeutics for this disease.

Elevation of the proinflammatory cytokine Interleukin-1 (IL-1) is an integral part of the local tissue reaction to central nervous system (CNS) insult. The discovery of increased IL-1 levels in patients following acute injury and in chronic neurodegenerative disease laid the foundation for two decades of research that has provided important details regarding IL-1's biology and function in the CNS. IL-1 elevation is now recognized as a critical component of the brain's patterned response to insults, termed neuroinflammation, and of leukocyte recruitment to the CNS. These processes are believed to underlie IL-1's function in the setting of acute brain injury, where it has been ascribed potential roles in repair as well as in exacerbation of damage. Explorations of IL-1's role in chronic neurodegenerative disease have mainly focused on Alzheimer disease (AD), where indirect evidence has implicated it in disease pathogenesis. However, recent observations in animal models challenge earlier assumptions that IL-1 elevation and resulting neuroinflammatory processes play a purely detrimental role in AD, and prompt a need for new characterizations of IL-1 function. Potentially adaptive functions of IL-1 elevation in AD warrant further mechanistic studies, and provide evidence that enhancement of these effects may help to alleviate the pathologic burden of disease.

Neuroinflammation is an important component of Alzheimer’s disease (AD) pathogenesis and has been implicated in neurodegeneration. Interleukin 1 (IL-1), a potent inflammatory cytokine in the central nervous system, is chronically upregulated in human AD and believed to serve as part of a vicious inflammatory cycle that drives AD pathology. To further understand the role of IL-1β in AD pathogenesis, we used an inducible model of sustained IL-1β overexpression (IL-1βXAT) developed in our laboratory. The triple transgenic mouse model of AD, which develops plaques and tangles later in its life cycle, was bred with IL-1βXAT mice and effects of IL-1β overexpression on AD pathology were assessed in F1 progeny. After 1 and 3 months of transgene expression, we found robust increases in tau phosphorylation despite an approximately 70–80% reduction in amyloid load and 4–6 fold increase in plaque associated microglia, as well as evidence of greater microglial activation at the site of inflammation. We also found evidence of increased p38MAPK and GSK3β activity, which are believed to contribute to tau phosphorylation. Thus neuroinflammation regulates amyloid and tau pathology in opposing fashions, suggesting that it provides a link between amyloid accumulation and changes in tau, and raising concerns about the use of immunomodulatory therapies in AD.

The proinflammatory cytokine interleukin-1␤ (IL-1␤

Glial activation and neuroinflammation occur in neurodegenerative disease and brain injury, however their presence in normal brain aging suggests that chronic neuroinflammation may be a factor in agerelated dementia. Few studies have investigated the impact of sustained elevation of hippocampal interleukin-1β, a pro-inflammatory cytokine upregulated during aging and Alzheimer's disease, on cognition in mice. We utilized the IL-1β XAT transgenic mouse to initiate bilateral hippocampal overexpression of interleukin-1β to determine the influence of sustained neuroinflammation independent of disease pathology. Fourteen days following transgene induction, adult male and female IL-1β XAT mice were tested on non-spatial and spatial versions of the Morris water maze. For the spatial component, one retention trial was conducted forty-eight hours after completion of a 3-day acquisition protocol (8 trials per day). Induction of IL-1β did not impact non-spatial learning, but was associated with delayed acquisition and decreased retention of the spatial task. These behavioral impairments were accompanied by robust reactive gliosis and elevated mRNA expression of inflammatory genes in the hippocampus. Our results suggest that prolonged neuroinflammation response per se may impact mnemonic processes and support the future application of IL-1β XAT transgenic mice to investigate chronic neuroinflammation in age-and pathology-related cognitive dysfunction. Keywordsneuroinflammation; water maze; IL-1β XAT transgenic mouse; hippocampus Chronic neuroinflammation is a prominent feature of Alzheimer's disease (AD) and is believed to contribute to the molecular cascade that ultimately manifests as cognitive dysfunction. It is well known that the single most important risk factor for AD is age. One reason for this association is that the progression from initial pathophysiological event to clinical detection is *Corresponding author: Amy H. Moore, Ph.D., Department of Biology, Carleton College, One North College Street, Northfield, MN 55057, Phone: 1.507.222.5981, Fax: 1.507.222.5757, amoore@carleton.edu. Neuroscience Section Editor: Behavioral Neuroscience Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2010 December 29. Published in final edited form as:Neuroscience. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript likely to be on the order of decades. Although glial activation is influenced by neuronal plaques and tangles, its presence in the aged brain (Nichols et al., 1993;P...