Interleukin-1 mediates Alzheimer and Lewy body pathologies

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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-I (IL-1) and other proinflarnmatory 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-Iβ or conditioned medium from sAPPα-activated microglia, with or without IL-I receptor antagonist. Slow-release pellets containing either IL-Iβ 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-Iβ. Cortical neurons treated with IL-Iβ showed a dose-dependent increase in sAPPα release, an effect that was enhanced in the presence of microglia. IL-Iβ also elevated the levels of α-synuclein, activated MAPK-p38, and phosphorylated tau; a concomitant decrease in levels of synaptophysin occurred. Delivery of IL-Iβ 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-I-expressing microglia with neurons that simultaneously overexpressed βAPP and contained both Lewy bodies and neurofibrillary tangles. Conclusion: Our findings suggest that IL-I drives production of substrates necessary for formation of the major neuropathological changes characteristic of AD/LBD. © 2006 Grifrin et al; licensee BioMed Central Ltd.




Griffin, W. S. T., Liu, L., Li, Y., Mrak, R. E., & Barger, S. W. (2006). Interleukin-1 mediates Alzheimer and Lewy body pathologies. Journal of Neuroinflammation, 3.

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