Abstract
BackgroundClinical 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.MethodsRat 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.ResultsActivation 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.ConclusionOur findings suggest that IL-1 drives production of substrates necessary for formation of the major neuropathological changes characteristic of AD/LBD.
Highlights
Clinical and neuropathological overlap between Alzheimer's (AD) and Parkinson's disease (PD) is well recognized
We propose that neuronal-glial interactions give rise to co-stimulation of expression and release of sAPPα from neurons and excessive expression of IL-1 in activated microglia and that these interactions are key links in an array of self-propagating, molecular and cellular interactions that are neurodegenerative in nature, triggering the overlapping clinicopathological spectrums of Alzheimer's disease (AD), LBD, and PD
In addition to its sufficiency for β-amyloid precursor protein (βAPP) expression and processing, we show here that IL-1 is necessary for the pathogenic signaling that activated microglia exert on neurons leading to diverse pathological changes, including elevation of α-synuclein levels
Summary
Clinical and neuropathological overlap between Alzheimer's (AD) and Parkinson's disease (PD) is 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). Dementia with Lewy bodies is a well-recognized entity featuring clinical cognitive impairment combined with the neuropathological finding of Lewy bodies in non-motor regions of the cerebral cortex. Such cortical Lewy bodies are often found in association with the amyloid plaques and neurofibrillary tangles pathognomonic for AD, and Lewy bodies correlate with clinical dementia in cases of mixed pathology [2]. They propose that "the mechanisms of Lewy bodies formation are identical regardless of the biological trigger."
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