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Cited by 261Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

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Early correlation of microglial activation with enhanced tumor necrosis factor-alpha and monocyte chemoattractant protein-1 expression specifically within the entorhinal cortex of triple transgenic Alzheimer's disease mice

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Janelsins, Michelle C, Mastrangelo, Michael A, Oddo, Salvatore, LaFerla, Frank M, Federoff, Howard J, Bowers, William J·2005·Journal of Neuroinflammation
DOI 10.1186/1742-2094-2-23PMC PMC1276812
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Abstract

Background: Alzheimer's disease is a complex neurodegenerative disorder characterized pathologically by a temporal and spatial progression of beta-amyloid (Aβ) deposition, neurofibrillary tangle formation, and synaptic degeneration. Inflammatory processes have been implicated in initiating and/or propagating AD-associated pathology within the brain, as inflammatory cytokine expression and other markers of inflammation are pronounced in individuals with AD pathology. The current study examines whether inflammatory processes are evident early in the disease process in the 3xTg-AD mouse model and if regional differences in inflammatory profiles exist. Methods: Coronal brain sections were used to identify Aβ in 2, 3, and 6-month 3xTg-AD and non-transgenic control mice. Quantitative real-time RT-PCR was performed on microdissected entorhinal cortex and hippocampus tissue of 2, 3, and 6-month 3xTg-AD and non-transgenic mice. Microglial/macrophage cell numbers were quantified using unbiased stereology in 3xTg-AD and non-transgenic entorhinal cortex and hippocampus containing sections. Results: We observed human Aβ deposition at 3 months in 3xTg-AD mice which is enhanced by 6 months of age. Interestingly, we observed a 14.8-fold up-regulation of TNF-α and 10.8-fold up-regulation of MCP-1 in the entorhinal cortex of 3xTg-AD mice but no change was detected over time in the hippocampus or in either region of non-transgenic mice. Additionally, this increase correlated with a specific increase in F4/80-positive microglia and macrophages in 3xTg-AD entorhinal cortex. Conclusion: Our data provide evidence for early induction of inflammatory processes in a model that develops amyloid and neurofibrillary tangle pathology. Additionally, our results link inflammatory processes within the entorhinal cortex, which represents one of the earliest AD-affected brain regions.

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Figure 1 Intracellular Aβ appears at 3 months and is enhanced by 6 months in 3xTg-AD mice. Coronal brain sections from 2, 3 and 6 month-old 3xTg-AD and non-transgenic mice were stained with human APP/Aβ-specific 6E10 antibody and developed using DAB. Panel A illustrates that the brains of 2 month-old 3xTg-AD mice are pre-pathologic, while at 3 months, hAPP/Aβ can be readily detected in both the entorhinal cortex and hippocampus of 3xTg-AD mice. By 6 months of age, 3xTg-AD mice exhibit further enhanced deposition of hAβ in both regions. Panel B identifies sections of entorhinal cortex and hippocampus from non-transgenic mice, which are not immunohistochemically positive for endogenous mouse Aβ, therefore indicating that the 6E10 antibody specifically detects transgene-driven expression of hAPP/Aβ in 3xTg-AD mice. The scale bars depict 50 μm. The insets represent 60× magnification.
Figure 1 Intracellular Aβ appears at 3 months and is enhanced by 6 months in 3xTg-AD mice. Coronal brain sections from 2, 3 and 6 month-old 3xTg-AD and non-transgenic mice were stained with human APP/Aβ-specific 6E10 antibody and developed using DAB. Panel A illustrates that the brains of 2 month-old 3xTg-AD mice are pre-pathologic, while at 3 months, hAPP/Aβ can be readily detected in both the entorhinal cortex and hippocampus of 3xTg-AD mice. By 6 months of age, 3xTg-AD mice exhibit further enhanced deposition of hAβ in both regions. Panel B identifies sections of entorhinal cortex and hippocampus from non-transgenic mice, which are not immunohistochemically positive for endogenous mouse Aβ, therefore indicating that the 6E10 antibody specifically detects transgene-driven expression of hAPP/Aβ in 3xTg-AD mice. The scale bars depict 50 μm. The insets represent 60× magnification.CC BY · PubMed Central
Figure 2 The 3xTg-AD entorhinal cortex harbors an increased number of macrophages/microglia at 6 months of age. Coronal brain sections from 2 and 6 month-old 3xTg-AD and control mice were stained with anti-F4/80 antibody and developed using DAB. (A) Qualitative image analysis reveals activation of F4/80-expressing macrophages and microglia specifically in the entorhinal cortex of 3xTg-AD mice at 6 months of age. (B) Unbiased quantitative stereologic analyses were performed on the entorhinal cortex to derive the total number of F4/80-positive cells. Error bars indicate standard deviation. N = 4 per genotype per time point. "*" indicates p < 0.008. The scale bar represents 50 μm.
Figure 2 The 3xTg-AD entorhinal cortex harbors an increased number of macrophages/microglia at 6 months of age. Coronal brain sections from 2 and 6 month-old 3xTg-AD and control mice were stained with anti-F4/80 antibody and developed using DAB. (A) Qualitative image analysis reveals activation of F4/80-expressing macrophages and microglia specifically in the entorhinal cortex of 3xTg-AD mice at 6 months of age. (B) Unbiased quantitative stereologic analyses were performed on the entorhinal cortex to derive the total number of F4/80-positive cells. Error bars indicate standard deviation. N = 4 per genotype per time point. "*" indicates p < 0.008. The scale bar represents 50 μm.CC BY · PubMed Central
Figure 3 The 3xTg-AD hippocampus does not have an increased number of macrophages/microglia at 6 months of age. Coronal brain sections from 2 and 6 month-old 3xTg-AD and control mice were stained with the anti-F4/80 antibody and developed using DAB. (A) Qualitative analyses shows little change in activation of microglia and macrophages in the hippocampus of 3xTg-AD or non-transgenic mice over time. (B) Unbiased stereology was performed on the hippocampal formation to determine total number of F4/80-positive cells. Error bars indicate standard deviation. N = 4 per genotype per time point. The scale bar represents 50 μm.
Figure 3 The 3xTg-AD hippocampus does not have an increased number of macrophages/microglia at 6 months of age. Coronal brain sections from 2 and 6 month-old 3xTg-AD and control mice were stained with the anti-F4/80 antibody and developed using DAB. (A) Qualitative analyses shows little change in activation of microglia and macrophages in the hippocampus of 3xTg-AD or non-transgenic mice over time. (B) Unbiased stereology was performed on the hippocampal formation to determine total number of F4/80-positive cells. Error bars indicate standard deviation. N = 4 per genotype per time point. The scale bar represents 50 μm.CC BY · PubMed Central

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Metadata

Authors
Janelsins, M. C., Mastrangelo, M. A., Oddo, S., LaFerla, F. M., Federoff, H. J., & Bowers, W. J.
Affiliations
  • University of Rochester Medicine (US)
  • University of California, Irvine (US)
Corresponding author
Bowers, William J
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2005-10-18
Volume
2
Issue
1
Pages
23-23
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/1742-2094-2-23
PMC
PMC1276812
OpenAlex
W2163115168
Cited by
260
References
41
Citations by year
2026: 2 · 2025: 9 · 2024: 22 · 2023: 13 · 2022: 13 · 2021: 8 · 2020: 18 · 2019: 13 · 2018: 14 · 2017: 14 · 2016: 12 · 2015: 18 · 2014: 11 · 2013: 13 · 2012: 15
FWCI
4.44
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health
  • National Institute on Aging (R01AG020204, R01AG023593)
  • National Institute of Neurological Disorders and Stroke (F31NS049995)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
Alzheimer's disease, microglial activation, neuroinflammation, 3xTg-AD mice, entorhinal cortex, hippocampus, amyloid-beta deposition, TNF-α, MCP-1, microglia/macrophages, F4/80, neurofibrillary tangles

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