The Role of ASC Specks as Essential Cofactor in Amyloid β-induced Pathophysiology
1 Department of Neurodegenerative Diseases and Gerontopsychiatry, University of Bonn
Neurodegenerative Diseases, particularly Alzheimer’s Disease (AD), become increasingly prevalent due to the demographic changes of most developed societies. Yet, the underlying pathogenesis of AD is still poorly understood. The deposition of Aβ fibrils and plaques in the brain is certain, and furthermore recent studies suggest a pivotal role of neuroinflammation. In our earlier studies we provided evidence that ASC speck release by pyroptotic microglia is mandatory for endogenous Aβ plaque formation in APP/PS1 transgenic mice.
Based on these findings we will demonstrate that ASC specks are necessary and sufficient cofactors to induce seeding and spreading of synthetic Aβ in murine models of AD in vivo. For this we used wild-type and APP/PS1 transgenic mice having received intrahippocampal injection of ASC, synthetic Aβ, co-injection of ASC and synthetic Aβ or APP/PS1 brain homogenate. Readout systems will be histopathological changes of the hippocampal region and biochemical analyses of Aβ plaque formation five months after the injections. In further experiments, we will analyse whether ASC specks are also sufficient cofactors to accelerate cognitive deterioration in murine models of AD in vivo. The experimental setting is identical, though the readout parameters will differ. The cognitive function and anxiety behaviour of the mice will be longitudinally studied exercising the Morris Water Maze and the Open Field Tests.
The outcome of this project will help us to clarify the role of ASC specks as an essential cofactor in Aβ-induced AD pathophysiology. ASC specks should be considered as a new therapeutic target in AD.