Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer's disease

Background: Inflammation is believed to play an important role in the pathology of Alzheimer's disease (AD) and cytokine production is a key pathologic event in the progression of inflammatory cascades. The current study characterizes the cytokine expression profile in the brain of two transgenic mouse models of AD (TgAPPsw and PS1/APPsw) and explores the correlations between cytokine production and the level of soluble and insoluble forms of A beta. Methods: Organotypic brain slice cultures from 15-month-old mice (TgAPPsw, PS1/APPsw and control littermates) were established and multiple cytokine levels were analyzed using the Bio-plex multiple cytokine assay system. Soluble and insoluble forms of A beta were quantified and A beta-cytokine relationships were analyzed. Results: Compared to control littermates, transgenic mice showed a significant increase in the following pro-inflammatory cytokines: TNF-alpha, IL-6, IL-12p40, IL-1 beta, IL-1 alpha and GM-CSF. TNF-alpha, IL6, IL-1 alpha and GM-CSF showed a sequential increase from control to TgAPPsw to PS1/APPsw suggesting that the amplitude of this cytokine response is dependent on brain A beta levels, since PS1/APPsw mouse brains accumulate more A beta than TgAPPsw mouse brains. Quantification of A beta levels in the same slices showed a wide range of A beta soluble: insoluble ratio values across TgAPPsw and PS1/APPsw brain slices. A beta-cytokine correlations revealed significant relationships between A beta 140, 1-42 (both soluble and insoluble) and all the above cytokines that changed in the brain slices. Conclusion: Our data confirm that the brains of transgenic APPsw and PS1/APPsw mice are under an active inflammatory stress, and that the levels of particular cytokines may be directly related to the amount of soluble and insoluble A beta present in the brain suggesting that pathological accumulation of A beta is a key driver of the neuroinflammatory response.