Browsing publications of the research group neuroinflammation and neurodegeneration (NIND) by Subjects
Now showing items 1-2 of 2
The APP Intracellular Domain Is Required for Normal Synaptic Morphology, Synaptic Plasticity, and Hippocampus-Dependent Behavior.The amyloid precursor protein family (APP/APLPs) has essential roles for neuromuscular synapse development and for the formation and plasticity of synapses within the CNS. Despite this, it has remained unclear whether APP mediates its functions primarily as a cell surface adhesion and signaling molecule or via its numerous proteolytic cleavage products. To address these questions, we followed a genetic approach and used APPΔCT15 knockin mice lacking the last 15 amino acids of APP, including the highly conserved YENPTY protein interaction motif. To circumvent functional compensation by the closely related APLP2, these mice were bred to an APLP2-KO background to generate APPΔCT15-DM double mutants. These APPΔCT15-DM mice were partially viable and displayed defects in neuromuscular synapse morphology and function with impairments in the ability to sustain transmitter release that resulted in muscular weakness. In the CNS, we demonstrate pronounced synaptic deficits including impairments in LTP that were associated with deficits in spatial learning and memory. Thus, the APP-CT15 domain provides essential physiological functions, likely via recruitment of specific interactors. Together with the well-established role of APPsα for synaptic plasticity, this shows that multiple domains of APP, including the conserved C-terminus, mediate signals required for normal PNS and CNS physiology. In addition, we demonstrate that lack of the APP-CT15 domain strongly impairs Aβ generation in vivo, establishing the APP C-terminus as a target for Aβ-lowering strategies.
NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice.Alzheimer's disease is the world's most common dementing illness. Deposition of amyloid-β peptide drives cerebral neuroinflammation by activating microglia. Indeed, amyloid-β activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1β maturation and subsequent inflammatory events. However, it remains unknown whether NLRP3 activation contributes to Alzheimer's disease in vivo. Here we demonstrate strongly enhanced active caspase-1 expression in human mild cognitive impairment and brains with Alzheimer's disease, suggesting a role for the inflammasome in this neurodegenerative disease. Nlrp3(-/-) or Casp1(-/-) mice carrying mutations associated with familial Alzheimer's disease were largely protected from loss of spatial memory and other sequelae associated with Alzheimer's disease, and demonstrated reduced brain caspase-1 and interleukin-1β activation as well as enhanced amyloid-β clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of amyloid-β in the APP/PS1 model of Alzheimer's disease. These results show an important role for the NLRP3/caspase-1 axis in the pathogenesis of Alzheimer's disease, and suggest that NLRP3 inflammasome inhibition represents a new therapeutic intervention for the disease.