Beta-amyloid-induced glial expression of both pro- and anti-inflammatory cytokines in cerebral cortex of aged transgenic Tg2576 mice with Alzheimer plaque pathology

To elucidate the mechanisms involved in beta-amyloid-mediated inflammation in Alzheimer's disease, transgenic Tg2576 mice containing as transgene the Swedish double mutation of human amyloid precursor protein 695, were examined for the expression pattern of various cytokines using double immunocytochemistry and laser scanning microscopy. Tg2576 mice studied at postnatal ages of 13, 16 and 19 months demonstrated an age-related accumulation of both senile and diffuse beta-amyloid plaques in neocortex and hippocampus. Reactive interleukin (IL)-1beta-immunoreactive astrocytes were found in close proximity to both fibrillary and diffuse beta-amyloid deposits detectable at very early stages of plaque development, while activated microglia appeared in and around fibrillary beta-amyloid plaques only. Subpopulations of reactive astrocytes also demonstrated immunolabeling for transforming growth factor (TGF)-beta1, TGF-beta3, and IL-10, already detectable in 13-month-old transgenic mouse brain, while a few IL-6-immunoreactive astrocytes were observed only at later stages of plaque development. The early beta-amyloid-mediated upregulation of IL-1beta, TGF-beta, and IL-10 in surrounding reactive astrocytes indicates the induction of both pro- and anti-inflammatory mechanisms. The transgenic approach used in this study may thus provide a useful tool to further disclose the in vivo mechanisms by which pro- and anti-inflammatory cytokines interact and/or contribute to the progression of Alzheimer's disease.     

β-Amyloid-induced glial expression of both pro- and anti-inflammatory cytokines in cerebral cortex of aged transgenic Tg2576 mice with Alzheimer plaque pathology

To elucidate the mechanisms involved in β-amyloid-mediated inflammation in Alzheimer’s disease, transgenic Tg2576 mice containing as transgene the Swedish double mutation of human amyloid precursor protein 695, were examined for the expression pattern of various cytokines using double immunocytochemistry and laser scanning microscopy. Tg2576 mice studied at postnatal ages of 13, 16 and 19 months demonstrated an age-related accumulation of both senile and diffuse β-amyloid plaques in neocortex and hippocampus. Reactive interleukin (IL)-1β-immunoreactive astrocytes were found in close proximity to both fibrillary and diffuse β-amyloid deposits detectable at very early stages of plaque development, while activated microglia appeared in and around fibrillary β-amyloid plaques only. Subpopulations of reactive astrocytes also demonstrated immunolabeling for transforming growth factor (TGF)-β1, TGF-β3, and IL-10, already detectable in 13-month-old transgenic mouse brain, while a few IL-6-immunoreactive astrocytes were observed only at later stages of plaque development. The early β-amyloid-mediated upregulation of IL-1β, TGF-β, and IL-10 in surrounding reactive astrocytes indicates the induction of both pro- and anti-inflammatory mechanisms. The transgenic approach used in this study may thus provide a useful tool to further disclose the in vivo mechanisms by which pro- and anti-inflammatory cytokines interact and/or contribute to the progression of Alzheimer’s disease.     

Induction of cytokines in glial cells surrounding cortical β-amyloid plaques in transgenic Tg2576 mice with Alzheimer pathology

β-Amyloid plaque deposition observed in brains from Alzheimer patients, might function as immune stimulus for glial/macrophages activation, which is supported by observations of activated microglia expressing interleukin (IL)-1β and elevated IL-6 immunoreactivity in close proximity to amyloid plaques. To elucidate the mechanisms involved in β-amyloid-mediated inflammation, transgenic mice (Tg2576) expressing high levels of the Swedish double mutation of human amyloid precursor protein and progressively developing typical β-amyloid plaques in cortical brain regions including gliosis and astrocytosis, were examined for the expression pattern of a number of cytokines.Using ribonuclease protection assay, interleukin (IL)-1α,-β, IL-1 receptor antagonist, IL-6, IL-10, IL-12, IL-18, interferon-γ, and macrophage migration inhibitory factor (MIF) mRNA were not induced in a number of cortical areas of Tg2576 mice regardless of the postnatal ages studied ranging between 2 and 13 months. Using immunocytochemistry for IL-1α,β, IL-6, tumor necrosis factor (TNF)-α, and macrophage chemotactic protein (MCP)-1, only IL-1β was found to be induced in reactive astrocytes surrounding β-amyloid deposits detected in 14-month-old Tg2576 mice. Using non-radioactive in situ hybridization glial fibrillary acidic protein (GFAP) mRNA was detected to be expressed by reactive astrocytes in close proximity to β-amyloid plaques. The local immune response detected around cortical β-amyloid deposits in transgenic Tg2576 mouse brain is seemingly different to that observed in brains from Alzheimer patients but may represent an initial event of chronic neuroinflammation at later stages of the disease.     

Aging-related increase in oxidative stress correlates with developmental pattern of beta-secretase activity and beta-amyloid plaque formation in transgenic Tg2576 mice with Alzheimer-like pathology

The molecular mechanisms of beta-amyloidogenesis in sporadic Alzheimer's disease are still poorly understood. To reveal whether aging-associated increases in brain oxidative stress and inflammation may trigger onset or progression of beta-amyloid deposition, a transgenic mouse (Tg2576) that express the Swedish double mutation of human amyloid precursor protein (APP) was used as animal model to study the developmental pattern of markers of oxidative stress and APP processing. In Tg2576 mouse brain, cortical levels of soluble beta-amyloid (1-40) and (1-42) steadily increased with age, but significant deposition of fibrillary beta-amyloid in cortical areas did not occur before postnatal age of 10 months. The slope of increase in cerebral cortical beta-secretase (BACE1) activities in Tg2576 mice between ages of 9 and 13 months was significantly higher as compared to that of the alpha-secretase, while the expression level of BACE1 protein and mRNA did not change with age. The activities of superoxide dismutase and glutathione peroxidase in cortical tissue from Tg2576 mice steadily increased from postnatal age 9-12 months. The levels of cortical nitric oxide, and reactive nitrogen species demonstrated peak values around 9 months of age, while the level of interleukin-1beta steadily increased from postnatal month 13 onwards. The developmental temporal coincidence of increased levels of reactive nitrogen species and antioxidative enzymes with the onset of beta-amyloid plaque deposition provides further evidence that developmentally and aging-induced alterations in brain oxidative status exhibit a major factor in triggering enhanced production and deposition of beta-amyloid, and potentially predispose to Alzheimer's disease.