Interferon-γ and tumor necrosis factor-α regulate amyloid-β plaque deposition and β-secretase expression in Swedish mutant APP transgenic mice
M Yamamoto, T Kiyota, M Horiba, JL Buescher… - The American journal of …, 2007 - Elsevier
M Yamamoto, T Kiyota, M Horiba, JL Buescher, SM Walsh, HE Gendelman, T Ikezu
The American journal of pathology, 2007•ElsevierReactive astrocytes and microglia in Alzheimer's disease surround amyloid plaques and
secrete proinflammatory cytokines that affect neuronal function. Relationship between
cytokine signaling and amyloid-β peptide (Aβ) accumulation is poorly understood. Thus, we
generated a novel Swedish β-amyloid precursor protein mutant (APP) transgenic mouse in
which the interferon (IFN)-γ receptor type I was knocked out (APP/GRKO). IFN-γ signaling
loss in the APP/GRKO mice reduced gliosis and amyloid plaques at 14 months of age …
secrete proinflammatory cytokines that affect neuronal function. Relationship between
cytokine signaling and amyloid-β peptide (Aβ) accumulation is poorly understood. Thus, we
generated a novel Swedish β-amyloid precursor protein mutant (APP) transgenic mouse in
which the interferon (IFN)-γ receptor type I was knocked out (APP/GRKO). IFN-γ signaling
loss in the APP/GRKO mice reduced gliosis and amyloid plaques at 14 months of age …
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-β peptide (Aβ) accumulation is poorly understood. Thus, we generated a novel Swedish β-amyloid precursor protein mutant (APP) transgenic mouse in which the interferon (IFN)-γ receptor type I was knocked out (APP/GRKO). IFN-γ signaling loss in the APP/GRKO mice reduced gliosis and amyloid plaques at 14 months of age. Aggregated Aβ induced IFN-γ production from co-culture of astrocytes and microglia, and IFN-γ elicited tumor necrosis factor (TNF)-α secretion in wild type (WT) but not GRKO microglia co-cultured with astrocytes. Both IFN-γ and TNF-α enhanced Aβ production from APP-expressing astrocytes and cortical neurons. TNF-α directly stimulated β-site APP-cleaving enzyme (BACE1) expression and enhanced β-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-γ and TNF-α activation of WT microglia suppressed Aβ degradation, whereas GRKO microglia had no changes. These results support the idea that glial IFN-γ and TNF-α enhance Aβ deposition through BACE1 expression and suppression of Aβ clearance. Taken together, these observations suggest that proinflammatory cytokines are directly linked to Alzheimer's disease pathogenesis.
Elsevier