Analysis Tools
nervous system
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• microglia from whole brains of 6-month-old mice exhibit a shift towards a pro-inflammatory state, as shown by a significant increase in the frequencies of CD45-mid/CD11b-positive microglia expressing CD86 (a pro-inflammatory marker) and Cxcr4hi (a chemokine receptor involved in inflammation)
• moreover, microglia produce more matrix metalloproteinase 9 (MMP-9), a microglia-enriched Abeta-degrading enzyme that can digest both soluble and fibrillar forms of amyloid beta (Abeta)
• however, microglial recruitment to plaques is normal and the overall levels of microgliosis and astrogliosis remain unaffected in the aged hippocampus and cortex
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• at 6 months of age, brains show a significantly lower amyloid beta (Abeta) plaque burden, as defined by the area of HJ3.4 coverage, in the hippocampus and cortex than in control mice hemizygous for Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas alone
• average plaque size is significantly decreased in the aged hippocampus while the number of plaques per 1000 um2 within the hippocampus is relatively normal
• aged mice have significantly fewer smaller plaques in the hippocampus (602-1301 um2) and cortex (600-1649 um2) than control mice
• brain sections co-stained with X-34 (beta-sheet-rich, dense core) and HJ3.4 (total Abeta) indicates significantly more compact plaques in the aged hippocampus
• in aged brains, full-length APP protein levels are relatively normal but C-terminal fragment alpha (CTF-alpha, C83) levels are significantly decreased while CTF-beta (C99) levels are reduced to a lesser extent, suggesting more efficient APP processing and/or degradation
• however, X-34-positive plaques in the cortex are similar to those in control mice and no differences in neuritic dystrophy are detected near plaques in the aged hippocampus or cortex
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• brain homogenates from 6-month-old mice show significantly increased protein levels of MMP-9 in the RAB-soluble fraction (enriched for secreted proteins) with no major changes detected in IDE, NEP or cathepsin B protein levels in this fraction
• MMP-9 protein levels are also significantly increased in RAB-soluble protein fraction of 6-week-old mice, prior to plaque accumulation
• cathepsin B levels are significantly reduced in the RIPA-soluble fraction which contains membrane-bound proteins, with no major changes detected in MMP-9, IDE, and NEP levels in this fraction
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homeostasis/metabolism
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• at 6 months of age, brains show a significantly lower amyloid beta (Abeta) plaque burden, as defined by the area of HJ3.4 coverage, in the hippocampus and cortex than in control mice hemizygous for Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas alone
• average plaque size is significantly decreased in the aged hippocampus while the number of plaques per 1000 um2 within the hippocampus is relatively normal
• aged mice have significantly fewer smaller plaques in the hippocampus (602-1301 um2) and cortex (600-1649 um2) than control mice
• brain sections co-stained with X-34 (beta-sheet-rich, dense core) and HJ3.4 (total Abeta) indicates significantly more compact plaques in the aged hippocampus
• in aged brains, full-length APP protein levels are relatively normal but C-terminal fragment alpha (CTF-alpha, C83) levels are significantly decreased while CTF-beta (C99) levels are reduced to a lesser extent, suggesting more efficient APP processing and/or degradation
• however, X-34-positive plaques in the cortex are similar to those in control mice and no differences in neuritic dystrophy are detected near plaques in the aged hippocampus or cortex
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• in vivo microdialysis of 8-week-old mice shows that baseline levels of soluble amyloid beta (Abeta) in the brain (hippocampal) interstitial fluid (ISF) are significantly lower than in control mice hemizygous for Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas alone
• after i.p. treatment with a gamma-secretase inhibitor to prevent new Abeta production, the elimination rate of soluble Abeta in brain ISF is significantly faster than in control mice, indicating that Abeta half-life is reduced prior to plaque accumulation
• however, decreased ISF Abeta levels are not due to altered amyloid precursor protein (APP) processing, as both expression of APP processing genes and protein levels of full-length APP and its C-terminal fragments are normal in 6-week-old brains
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• brain homogenates from 6-month-old mice show significantly increased protein levels of MMP-9 in the RAB-soluble fraction (enriched for secreted proteins) with no major changes detected in IDE, NEP or cathepsin B protein levels in this fraction
• MMP-9 protein levels are also significantly increased in RAB-soluble protein fraction of 6-week-old mice, prior to plaque accumulation
• cathepsin B levels are significantly reduced in the RIPA-soluble fraction which contains membrane-bound proteins, with no major changes detected in MMP-9, IDE, and NEP levels in this fraction
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immune system
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• microglia from whole brains of 6-month-old mice exhibit a shift towards a pro-inflammatory state, as shown by a significant increase in the frequencies of CD45-mid/CD11b-positive microglia expressing CD86 (a pro-inflammatory marker) and Cxcr4hi (a chemokine receptor involved in inflammation)
• moreover, microglia produce more matrix metalloproteinase 9 (MMP-9), a microglia-enriched Abeta-degrading enzyme that can digest both soluble and fibrillar forms of amyloid beta (Abeta)
• however, microglial recruitment to plaques is normal and the overall levels of microgliosis and astrogliosis remain unaffected in the aged hippocampus and cortex
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hematopoietic system
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• microglia from whole brains of 6-month-old mice exhibit a shift towards a pro-inflammatory state, as shown by a significant increase in the frequencies of CD45-mid/CD11b-positive microglia expressing CD86 (a pro-inflammatory marker) and Cxcr4hi (a chemokine receptor involved in inflammation)
• moreover, microglia produce more matrix metalloproteinase 9 (MMP-9), a microglia-enriched Abeta-degrading enzyme that can digest both soluble and fibrillar forms of amyloid beta (Abeta)
• however, microglial recruitment to plaques is normal and the overall levels of microgliosis and astrogliosis remain unaffected in the aged hippocampus and cortex
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cellular
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• microglia from whole brains of 6-month-old mice exhibit a shift towards a pro-inflammatory state, as shown by a significant increase in the frequencies of CD45-mid/CD11b-positive microglia expressing CD86 (a pro-inflammatory marker) and Cxcr4hi (a chemokine receptor involved in inflammation)
• moreover, microglia produce more matrix metalloproteinase 9 (MMP-9), a microglia-enriched Abeta-degrading enzyme that can digest both soluble and fibrillar forms of amyloid beta (Abeta)
• however, microglial recruitment to plaques is normal and the overall levels of microgliosis and astrogliosis remain unaffected in the aged hippocampus and cortex
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