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Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer's disease.

ABSTRACT: BACKGROUND: Inflammation is believed to play an important role in the pathology of Alzheimer's disease (AD) and cytokine production is a key pathologic event in the progression of inflammatory cascades. The current study characterizes the cytokine expression profile in the brain of two transgenic mouse models of AD (TgAPPsw and PS1/APPsw) and explores the correlations between cytokine production and the level of soluble and insoluble forms of Abeta. METHODS: Organotypic brain slice cultures from 15-month-old mice (TgAPPsw, PS1/APPsw and control littermates) were established and multiple cytokine levels were analyzed using the Bio-plex multiple cytokine assay system. Soluble and insoluble forms of Abeta were quantified and Abeta-cytokine relationships were analyzed. RESULTS: Compared to control littermates, transgenic mice showed a significant increase in the following pro-inflammatory cytokines: TNF-alpha, IL-6, IL-12p40, IL-1beta, IL-1alpha and GM-CSF. TNF-alpha, IL-6, IL-1alpha and GM-CSF showed a sequential increase from control to TgAPPsw to PS1/APPsw suggesting that the amplitude of this cytokine response is dependent on brain Abeta levels, since PS1/APPsw mouse brains accumulate more Abeta than TgAPPsw mouse brains. Quantification of Abeta levels in the same slices showed a wide range of Abeta soluble:insoluble ratio values across TgAPPsw and PS1/APPsw brain slices. Abeta-cytokine correlations revealed significant relationships between Abeta1-40, 1-42 (both soluble and insoluble) and all the above cytokines that changed in the brain slices. CONCLUSION: Our data confirm that the brains of transgenic APPsw and PS1/APPsw mice are under an active inflammatory stress, and that the levels of particular cytokines may be directly related to the amount of soluble and insoluble Abeta present in the brain suggesting that pathological accumulation of Abeta is a key driver of the neuroinflammatory response.

SUBMITTER: Patel NS

PROVIDER: S-EPMC555557 | biostudies-literature | 2005 Mar

REPOSITORIES: biostudies-literature

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Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer's disease.

Patel Nikunj S NS Paris Daniel D Mathura Venkatarajan V Quadros Amita N AN Crawford Fiona C FC Mullan Michael J MJ

Journal of neuroinflammation 20050311 1

BACKGROUND: Inflammation is believed to play an important role in the pathology of Alzheimer's disease (AD) and cytokine production is a key pathologic event in the progression of inflammatory cascades. The current study characterizes the cytokine expression profile in the brain of two transgenic mouse models of AD (TgAPPsw and PS1/APPsw) and explores the correlations between cytokine production and the level of soluble and insoluble forms of Abeta. METHODS: Organotypic brain slice cultures from ...[more]

PMID: 15762998

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Project description:An early and sizeable loss of basal forebrain cholinergic neurons is a well-characterized feature associated with measurable deficits in spatial learning and cognitive impairment in patients with Alzheimer's disease. In addition, pro-inflammatory glial cells such as astrocytes and microglia may play a key role in the neurodegenerative cascade of Alzheimer's disease and tauopathies. We recently presented two mouse models: Line 1, expressing the truncated tau fragment identified as the core of the Alzheimer's paired helical filament, and Line 66, expressing full-length human tau carrying a double mutation (P301S and G335D). Line 1 mice have a pathology that is akin to Alzheimer's, whilst Line 66 resembles frontotemporal lobar degeneration. However, their cholinergic and inflammatory phenotypes remain elusive. We performed histological evaluation of choline acetyltransferase, acetylcholinesterase, p75 neurotrophin receptor, microglial ionized calcium binding adaptor molecule 1 and astrocytic glial fibrillary acidic protein in the basal forebrain, hippocampus and cortex of these models. A significant lowering of choline acetyltransferase-positive neurons and p75-positive neurons in the basal forebrain of Line 1 at 3, 6 and 9 months was observed in two independent studies, alongside a significant decrease in acetylcholinesterase staining in the cortex and hippocampus. The reductions in choline acetyltransferase positivity varied between 30% and 50% at an age when Line 1 mice show spatial learning impairments. Furthermore, an increase in microglial ionized calcium binding adaptor molecule 1 staining was observed in the basal forebrain, hippocampus and entorhinal cortex of Line 1 at 6 months. Line 66 mice displayed an intact cholinergic basal forebrain, and no difference in p75-positive neurons at 3 or 9 months. In addition, Line 66 exhibited significant microglial ionized calcium binding adaptor molecule 1 increase in the basal forebrain and hippocampus, suggesting a prominent neuroinflammatory profile. Increased concentrations of microglial interleukin-1β and astrocytic complement 3 were also seen in the hippocampus of both Line 1 and Line 66. The cholinergic deficit in Line 1 mice confirms the Alzheimer's disease-like phenotype in Line 1 mice, whilst Line 66 revealed no measurable change in total cholinergic expression, a phenotypic trait of frontotemporal lobar degeneration. These two transgenic lines are therefore suitable for discriminating mechanistic underpinnings between the Alzheimer's and frontotemporal lobar degeneration-like phenotypes of these mice.

Dataset Information

Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer's disease.

Publications

Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer's disease.

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