General statements



Inflammasome activation in Alzheimer’s disease


In brains of Alzheimer’s disease (AD) patients, deposits of pathological proteinaceous aggregates (senile plaques) surrounded by activated microglia cells are characteristic histopathological features. Senile plaques appear in the grey matter and consist mainly of extracellular Amyloid beta peptide (Aβ). In addition, so-called neurofibrillary tangles are found that consist of the hyperphosphorylated aggregated form of the microtubule-associated protein tau. Aβ can induce microglia to produce pro-inflammatory cytokines, chemokines and neurotoxic factors, all of which are believed to contribute to neurodegeneration, eventually resulting in progressive cognitive and motor impairment.

We found that the aggregated forms of Aβ led to the activation of a cytosolic receptor complex, termed the NLRP3 inflammasome. Inflammasomes control the activity of the inflammatory caspase-1, which is known to catalytically process the precursors of IL-1β cytokine family members. Notably, the activity of the NLRP3 inflammasome was critical for the secretion of neurotoxic factors, including NO and TNFα, as well as for chemokines. Consistently, ablation of the caspase-1 activating pathway or ablation of IL-1 signaling components led to greatly diminished microglial recruitment to injected Aβ in the brain, suggesting that the NLRP3 inflammasome pathway plays a critical role in the development of inflammation and neurotoxicity in vivo.

Here, we propose to test the in vivo relevance of the recognition of aggregated peptides by the NLRP3 inflammasome by crossing double transgenic mice expressing a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9) with mice deficient in critical components of the inflammasome pathway (NLRP3, ASC, caspase-1 and IL-1 receptor). In addition, we will establish a treatment model that allows testing the effect of anti-IL-1 treatment on the development of AD. These mice will be analyzed for clinical signs of AD and histopathological changes in the brain. These studies will enhance our understanding of the roles of inflammasomes and IL-1 cytokines in the pathophysiology of AD.