In vivo and in vitro evidence supporting a role for the inflammatory cytokine interleukin-1 as a driving force in Alzheimer pathogenesis

Abstract

Interleukin-1 (IL-1), an inflammatory cytokine overexpressed in the neuritic plaques of Alzheimer's disease, activates astrocytes and enhances production and processing of (β-amyloid precursor protein (β-APP). Activated astrocytes, overexpressing S100β, are a prominent feature of these neuritic plaques, and the neurite growth-promoting properties of S100β have been implicated in the formation of dystrophic neurites overexpressing β-APP in neuritic plaques. These facts collectively suggest that elevated levels of the inflammatory cytokine IL-1 drive S100β and β-APP overexpression and dystrophic neurite formation in Alzheimer's disease. To more directly assess this driver potential for IL-1, we analyzed IL-1 induction of S100β expression in vivo and in vitro, and of β-APP expression in vivo. Synthetic IL-1β was injected into the right cerebral hemispheres of 13 rats. Nine additional rats were injected with phosphate-buffered saline, and seven rats served as uninjected controls. The number of astrocytes expressing detectable levels of S100β in tissue sections from IL-1-injected brains was 1.5 fold that of either control group (p < 0.01), while tissue S100β levels were approximately threefold that of controls (p < 0.05). The tissue levels of two β-APP isoforms (approximately 130 and 135 kDa) were also significantly elevated in IL-1-injected brains (p < 0.05). C6 glioma cells, treated in vitro for 24 h with either IL-1β or IL-1α, showed significant increases in both S100β and S100β mRNA levels. These results provide evidence that IL-1 upregulates both S100β and β-APP expression, in vivo and in vitro, and support the idea that overexpression of IL-1 in Alzheimer's disease drives astrocytic overexpression of S100β, favoring the growth of dystrophic neurites necessary for evolution of diffuse amyloid deposits into neuritic β-amyloid plaques. KeywordsInterleukin-1; S100β; β-Amyloid precursor protein; Alzheimer's disease; Down's syndrome; Rats; C6 glioma cellsThe global intellectual decline of Alzheimer's disease is accompanied by a profusion of microscopic brain lesions that contain extracellular fibrillar material in a β-pleated sheet Copyright © 1996 conformation (β-amyloid), abnormal neuronal processes ("dystrophic" neurites) overexpressing β-amyloid precursor protein (β-APP), and activated glia (astrocytes and microglia). The possible interactions of these plaque-associated astrocytes and microglia, their armamentarium of overexpressed cytokines and other molecules, and the known actions of these cytokines and molecules bear sufficient parallels to chronic, focal inflammatory processes found outside the nervous system to suggest that the basic driving pathophysiological mechanism in Alzheimer's disease is fundamentally an inflammatory one (21).The plaques of Alzheimer's disease are thought to originate as diffuse deposits of nonpleated amyloid protein ('diffuse nonneuritic' plaques) that progress to more classic 'diffuse neuritic' plaques (commonly referred to as immature plaques) composed of β-pleated amyl...

Interleukin 1 receptor antagonist knockout mice show enhanced microglial activation and neuronal damage induced by intracerebroventricular infusion of human β-amyloid

“…This is not unexpected given the array of potentially detrimental molecules produced by the CNS in response to increased production of IL-1. For example, IL-1β and/or IL-1α have been implicated in the production of other pro-inflammatory cytokines such as S100B [14]. Furthermore, IL-1β can stimulate glial iNOS production [15], which in turn can greatly increase the oxidative stress experienced by the brain and potentially lead to neuronal damage through protein nitration pathways [25].…”

The role of inflammasome in Alzheimer's disease

“…Additionally, IL-1β has been found to increase the release of S100B from an astroglioma cell line and the plaque-associated activated astrocytes in the primary cortex that promote neuronal APP synthesis (Li et al, 2011; Liu et al, 2005). Injecting IL-1β into the cerebral hemisphere upregulates the levels of APP and amyloidogenesis (Sheng et al, 1996). Furthermore, several studies demonstrate that IL-1β can induce the phosphorylation of the tau protein and mediate the formation of neurofibrillary tangles through the MAPK-p38 pathway (Griffin et al, 2006; Salminen et al, 2008).…”

Arundic Acid (ONO-2506) Ameliorates Delayed Ischemic Brain Damage by Preventing Astrocytic Overproduction of S100B

“…Activated astrocytes together with microglia, neurons and endothelial cells produce a wide variety of biologically active substances [27,29], and participate in the creation of the third wave of gene expression after ischemia [31,36,189,190]. Among the cytokines produced by microglia, IL-1β has been shown to play an important role in the augmentation of inflammatory processes concurrent with ischemic brain damage [191,192]. Our results with arundic acid indicate that the role of astrocytic S100B overexpression is no less important than that of IL-1β.…”