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and Tumor Necrosis Factor-
Regulate Amyloid-ß Plaque Deposition and ß-Secretase Expression in Swedish Mutant APP Transgenic Mice
From the Center for Neurovirology and Neurodegenerative Disorders and the Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska
Reactive astrocytes and microglia in Alzheimer’s disease surround amyloid plaques and secrete proinflammatory cytokines that affect neuronal function. Relationship between cytokine signaling and amyloid-ß peptide (Aß) accumulation is poorly understood. Thus, we generated a novel Swedish ß-amyloid precursor protein mutant (APP) transgenic mouse in which the interferon (IFN)-
receptor type I was knocked out (APP/GRKO). IFN- signaling loss in the APP/GRKO mice reduced gliosis and amyloid plaques at 14 months of age. Aggregated Aß induced IFN- production from co-culture of astrocytes and microglia, and IFN- elicited tumor necrosis factor (TNF)-
secretion in wild type (WT) but not GRKO microglia co-cultured with astrocytes. Both IFN- and TNF- enhanced Aß production from APP-expressing astrocytes and cortical neurons. TNF- directly stimulated ß-site APP-cleaving enzyme (BACE1) expression and enhanced ß-processing of APP in astrocytes. The numbers of reactive astrocytes expressing BACE1 were increased in APP compared with APP/GRKO mice in both cortex and hippocampus. IFN- and TNF- activation of WT microglia suppressed Aß degradation, whereas GRKO microglia had no changes. These results support the idea that glial IFN- and TNF- enhance Aß deposition through BACE1 expression and suppression of Aß clearance. Taken together, these observations suggest that proinflammatory cytokines are directly linked to Alzheimer’s disease pathogenesis.
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