Research

Interleukin-1 mediates Alzheimer and Lewy body pathologies

W Sue T Griffin^1,3,4,5 , Ling Liu¹ , Yuekui Li¹ , Robert E Mrak^2,3 and Steven W Barger^1,3,4

¹  Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA

²  Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA

³  Department of Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA

⁴  Geriatric Research, Education and Clinical Center, Department of Veterans' Affairs Medical Center, Little Rock, Arkansas 72205, USA

⁵  Mental Illness Research Education Center, Department of Veterans' Affairs Medical Center, Little Rock, Arkansas 72205, USA

author email corresponding author email

Journal of Neuroinflammation 2006, 3:5doi:10.1186/1742-2094-3-5

Published:	16 March 2006

Abstract

Background

Clinical and neuropathological overlap between Alzheimer's (AD) and Parkinson's disease (PD) is now well recognized. Such cases of concurrent AD and Lewy body disease (AD/LBD) show neuropathological changes that include Lewy bodies (α-synuclein aggregates), neuritic amyloid plaques, and neurofibrillary tangles (hyperphosphorylated tau aggregates). The co-occurrence of these clinical and neuropathological changes suggests shared pathogenic mechanisms in these diseases, previously assumed to be distinct. Glial activation, with overexpression of interleukin-1 (IL-1) and other proinflammatory cytokines, has been increasingly implicated in the pathogenesis of both AD and PD.

Methods

Rat primary cultures of microglia and cortical neurons were cultured either separately or as mixed cultures. Microglia or cocultures were treated with a secreted fragment (sAPPα) of the β-amyloid precursor protein (βAPP). Neurons were treated with IL-1β or conditioned medium from sAPPα-activated microglia, with or without IL-1 receptor antagonist. Slow-release pellets containing either IL-1β or bovine serum albumin (control) were implanted in cortex of rats, and mRNA for various neuropathological markers was analyzed by RT-PCR. Many of the same markers were assessed in tissue sections from human cases of AD/LBD.

Results

Activation of microglia with sAPPα resulted in a dose-dependent increase in secreted IL-1β. Cortical neurons treated with IL-1β showed a dose-dependent increase in sAPPα release, an effect that was enhanced in the presence of microglia. IL-1β also elevated the levels of α-synuclein, activated MAPK-p38, and phosphorylated tau; a concomitant decrease in levels of synaptophysin occurred. Delivery of IL-1β by slow-release pellets elevated mRNAs encoding α-synuclein, βAPP, tau, and MAPK-p38 compared to controls. Finally, human cases of AD/LBD showed colocalization of IL-1-expressing microglia with neurons that simultaneously overexpressed βAPP and contained both Lewy bodies and neurofibrillary tangles.

Conclusion

Our findings suggest that IL-1 drives production of substrates necessary for formation of the major neuropathological changes characteristic of AD/LBD.