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Janelsins, MC, Mastrangelo, MA, Oddo, S, LaFerla, FM, Federoff, HJ and Bowers, WJ. 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. J Neuroinflammation 2: 23

Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
Journal of Neuroinflammation (Impact Factor: 5.41). 11/2005; 2(1):23. DOI: 10.1186/1742-2094-2-23
Source: PubMed

ABSTRACT

Alzheimer's disease is a complex neurodegenerative disorder characterized pathologically by a temporal and spatial progression of beta-amyloid (Abeta) 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.
Coronal brain sections were used to identify Abeta 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.
We observed human Abeta 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-alpha 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.
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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    • "Given these caveats, TNF-α is upregulated , co-localized with amyloid plaques, and neurotoxic in mouse models that recapitulate specific human AD-related pathologies. For instance, the triple transgenic mouse model of AD (3xTg-AD) that harbors three familial-linked AD mutations (APP swe , PS1 M146V , and Tau P301L ) and progressively develops amyloid and tau pathologies exhibits increased TNF-α and monocyte chemoattractant protein-1 (MCP-1) transcript levels, as well as increased numbers of activated microglia, in the entorhinal cortex at an age preceding appearance of plaque and tangle pathologies (Janelsins et al. 2005). The amyloidogenic Tg2576 mouse model develops Aβ plaques, increased TNF-α immunoreactivity , and glial cell clustering adjacent to fibrillar plaques (Mehlhorn et al. 2000). "

    Full-text · Dataset · Sep 2014
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    • "Given these caveats, TNF-α is upregulated , co-localized with amyloid plaques, and neurotoxic in mouse models that recapitulate specific human AD-related pathologies. For instance, the triple transgenic mouse model of AD (3xTg-AD) that harbors three familial-linked AD mutations (APP swe , PS1 M146V , and Tau P301L ) and progressively develops amyloid and tau pathologies exhibits increased TNF-α and monocyte chemoattractant protein-1 (MCP-1) transcript levels, as well as increased numbers of activated microglia, in the entorhinal cortex at an age preceding appearance of plaque and tangle pathologies (Janelsins et al. 2005). The amyloidogenic Tg2576 mouse model develops Aβ plaques, increased TNF-α immunoreactivity , and glial cell clustering adjacent to fibrillar plaques (Mehlhorn et al. 2000). "

    Full-text · Dataset · Sep 2014
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    • "It has been shown that innate immune receptors, such as toll-like receptor and lipopolysaccharide (LPS) receptor (CD14), are upregulated in the human AD brain (Letiembre et al., 2009). Furthermore, it is well known that most of the AD transgenic mouse models exhibit significant enhancement of neuroinflammation around amyloid plaques, like those in the human AD brain (Frautschy et al., 1998; Matsuoka et al., 2001; Janelsins et al., 2005), and its severity increases with progression of pathological amyloid with age (Sheng et al., 2000). Importantly, some markers of glial activation are elevated even before the development of amyloid deposition, implying that neuroinflammation precedes typical AD neuropathological changes and has some causative effect in AD pathogenesis (Sheng et al., 2000). "
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