Alzheimer´s Disease (AD) is the world’s most common dementing illness. Deposition of amyloid beta peptide (Aβ) drives cerebral neuroinflammation by activating microglia1,2. Indeed, Aβ activation of the NLRP3 inflammasome in microglia is fundamental for IL-1β maturation and subsequent inflammatory events3. However, it remains unknown whether NLRP3 activation contributes to AD in vivo. Here, we demonstrate strongly enhanced active caspase-1 expression in human MCI and AD brains suggesting a role for the inflammasome in this neurodegenerative disease. NLRP3−/− or caspase-1−/− mice carrying mutations associated with familiar AD were largely protected from loss of spatial memory and other AD-associated sequelae and demonstrated reduced brain caspase-1 and IL-1β activation as well as enhanced Aβ clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of Aβ in the APP/PS1 model of Alzheimer’s disease. These results reveal an important role for the NLRP3 / caspase-1 axis in AD pathogenesis, and suggest that NLRP3 inflammasome inhibition represents a novel therapeutic intervention for AD.

Alzheimer's disease is characterized by the accumulation of beta-amyloid in plaques, aggregation of hyperphosphorylated tau in neurofibrillary tangles and neuroinflammation, together resulting in neurodegeneration and cognitive decline 1 . The NLRP3 inflammasome assembles inside of microglia upon activation, leading to increased cleavage and activity of caspase-1 and downstream IL-1β release 2 . While the NLRP3 inflammasome was shown to be essential for the development and progression of beta-amyloid pathology in mice 3 , the precise impact on tau pathology remains elusive. Here we show that loss of NLRP3 inflammasome function reduced tau hyperphosphorylation and aggregation by regulating tau kinases and phosphatases. Tau activated the NLRP3 inflammasome and intracerebral injection of fibrillar beta-amyloid-containing brain *

The spreading of pathology within and between brain areas is a hallmark of neurodegenerative disorders. In patients with Alzheimer's disease, deposition of amyloid-β is accompanied by activation of the innate immune system and involves inflammasome-dependent formation of ASC specks in microglia. ASC specks released by microglia bind rapidly to amyloid-β and increase the formation of amyloid-β oligomers and aggregates, acting as an inflammation-driven cross-seed for amyloid-β pathology. Here we show that intrahippocampal injection of ASC specks resulted in spreading of amyloid-β pathology in transgenic double-mutant APPPSEN1 mice. By contrast, homogenates from brains of APPPSEN1 mice failed to induce seeding and spreading of amyloid-β pathology in ASC-deficient APPPSEN1 mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloid-β pathology in APPPSEN1 mice. These findings support the concept that inflammasome activation is connected to seeding and spreading of amyloid-β pathology in patients with Alzheimer's disease.

Microglia are the CNS resident immune cells that react to misfolded proteins through pattern recognition receptor ligation and activation of inflammatory pathways. Here, we studied how microglia handle and cope with a-synuclein (a-syn) fibrils and their clearance. We found that microglia exposed to a-syn establish a cellular network through the formation of F-actin-dependent intercellular connections, which transfer a-syn from overloaded microglia to neighboring naive microglia where the a-syn cargo got rapidly and effectively degraded. Lowering the a-syn burden attenuated the inflammatory profile of microglia and improved their survival. This degradation strategy was compromised in cells carrying the LRRK2 G2019S mutation. We confirmed the intercellular transfer of a-syn assemblies in microglia using organotypic slice cultures, 2-photon microscopy, and neuropathology of patients. Together, these data identify a mechanism by which microglia create an ''on-demand'' functional network in order to improve pathogenic a-syn clearance. ll