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Longitudinal investigation of neuroinflammation and metabolite profiles in the APPswe ×PS1Δe9 transgenic mouse model of Alzheimer's disease.

Aisling Chaney, Martin Bauer, Daniela Bochicchio, Alison Smigova, Michael Kassiou et al.
Other Journal of neurochemistry 2018 30 उद्धरण
PubMed DOI PDF
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Study Design

अध्ययन प्रकार
Other
जनसंख्या
Animal model (rodents)
अवधि
77.9 weeks
हस्तक्षेप
Longitudinal investigation of neuroinflammation and metabolite profiles in the APPswe ×PS1Δe9 transgenic mouse model of Alzheimer's disease. None
तुलनित्र
None
प्राथमिक परिणाम
None
प्रभाव की दिशा
Positive
पूर्वाग्रह का जोखिम
Unclear

Abstract

There is increasing evidence linking neuroinflammation to many neurological disorders including Alzheimer's disease (AD); however, its exact contribution to disease manifestation and/or progression is poorly understood. Therefore, there is a need to investigate neuroinflammation in both health and disease. Here, we investigate cognitive decline, neuroinflammatory and other pathophysiological changes in the APPswe ×PS1Δe9 transgenic mouse model of AD. Transgenic (TG) mice were compared to C57BL/6 wild type (WT) mice at 6, 12 and 18 months of age. Neuroinflammation was investigated by [18 F]DPA-714 positron emission tomography and myo-inositol levels using 1 H magnetic resonance spectroscopy (MRS) in vivo. Neuronal and cellular dysfunction was investigated by looking at N-acetylaspartate (NAA), choline-containing compounds, taurine and glutamate also using MRS. Cognitive decline was first observed at 12 m of age in the TG mice as assessed by working memory tests . A significant increase in [18 F]DPA-714 uptake was seen in the hippocampus and cortex of 18 m-old TG mice when compared to age-matched WT mice and 6 m-old TG mice. No overall effect of gene was seen on metabolite levels; however, a significant reduction in NAA was observed in 18 m-old TG mice when compared to WT. In addition, age resulted in a decrease in glutamate and an increase in choline levels. Therefore, we can conclude that increased neuroinflammation and cognitive decline are observed in TG animals, whereas NAA alterations occurring with age are exacerbated in the TG mice. These results support the role of neuroinflammation and metabolite alteration in AD and in ageing.

संक्षेप में

Increased neuroinflammation and cognitive decline are observed in TG animals, whereas NAA alterations occurring with age are exacerbated in the TG mice, which support the role of neuro inflammation and metabolite alteration in AD and in ageing.

Full Text

Longitudinal investigation 1 of neuroinflammation and metabolite profiles in the APPswe×PS1Δe9 transgenic mouse model of Alzheimer’s disease.

Chaney A.1,2*, Bauer M.3†, Bochicchio D.2†, Smigova A.1,2, Kassiou M.4, Davies K.E.14 , Williams S.R.1, Boutin H.1,2.

  1. 1 Centre for Imaging Science, Faculty of Biology, Medicine and Health and Manchester Academic Health Sciences Centre University of Manchester, Manchester, M13 9PT, UK
  2. 2 Wolfson Molecular Imaging Centre, Faculty of Biology, Medicine and Health and Manchester Academic Health Sciences Centre, University of Manchester, Manchester, M20 3LJ, UK. 3Medical University Vienna, Department of Clinical Pharmacology, Waehringer Guertel 1820, 1090 Vienna, Austria. 4School of Chemistry, University of Sydney, NSW 2006 Australia. † Contributed equally to the work

* Current address: 3165 Porter Drive, Stanford University, Palo Alto, CA, 94304.

Corresponding Author: Dr Hervé Boutin, Wolfson Molecular Imaging Centre, 27 Palatine Road, Manchester, M20 3LJ, UK Email: [email protected] Tel: +44 161 275 0078 Fax: +44 161 275 0003

18S U V [F ]D P A -714

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Supplementary Figure 2: [18F]DPA-714 standard uptake value in the cerebellum of WT and APPswe×PS1Δe9 mice at 6 (WT n=10, TG=7), 12 (WT n=8, TG=9) and 18 months (WT n=10, TG=9) of age. Results are

expressed as mean±SD. Statistical analysis was performed using two-way ANOVA followed by Sidak’s post-

hoc analysis (*p≤0.05).

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Figures

Figure 1

Longitudinal experimental design for investigating neuroinflammation and metabolite changes in the APPswe x PS1de9 transgenic Alzheimer's disease mouse model across multiple age time points.

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Figure 2

Microglial activation markers measured longitudinally in the transgenic Alzheimer's model, showing progressive neuroinflammatory changes that correlate with amyloid plaque accumulation over time.

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Figure 3

Astrocyte reactivity (GFAP immunostaining) in the APPswe x PS1de9 mouse brain at different ages, demonstrating increasing astrogliosis alongside advancing Alzheimer's-like pathology.

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Figure 4

Pro-inflammatory cytokine profiles in the transgenic Alzheimer's mouse brain measured at sequential time points, revealing a progressive neuroinflammatory signature associated with disease progression.

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Figure 5

Anti-inflammatory cytokine and growth factor levels in the APPswe x PS1de9 model over time, showing alterations in the neuroprotective signaling that may counteract neuroinflammation.

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Figure 6

Metabolite concentration data from the longitudinal Alzheimer's mouse model, tracking neurochemical changes in brain regions affected by amyloid pathology.

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Figure 7

Immunohistochemical analysis of neuroinflammatory markers in specific brain regions of the APPswe x PS1de9 transgenic mice, comparing age-matched wild-type and transgenic animals.

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Figure 8

Quantification of amyloid plaque burden and associated microglial clustering in the transgenic Alzheimer's model across the studied age range.

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Figure 9

Metabolite concentration data from the longitudinal Alzheimer's mouse model, tracking neurochemical changes in brain regions affected by amyloid pathology.

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Figure 10

Immunohistochemical analysis of neuroinflammatory markers in specific brain regions of the APPswe x PS1de9 transgenic mice, comparing age-matched wild-type and transgenic animals.

micrograph

Figure 11

MRS (magnetic resonance spectroscopy) data from the Alzheimer's transgenic mouse brain, detecting metabolite ratios that reflect neuronal integrity and glial activation status.

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Figure 12

Correlation analysis between neuroinflammatory marker levels and metabolite concentrations in the APPswe x PS1de9 mouse model, suggesting mechanistic links between inflammation and metabolic disruption.

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Figure 13

Regional brain analysis comparing hippocampal and cortical neuroinflammatory profiles in the transgenic Alzheimer's model at an intermediate age time point.

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Figure 14

Longitudinal tracking of specific metabolite ratios (such as NAA/Cr or myo-inositol/Cr) in the Alzheimer's transgenic mouse model, used as biomarkers of neuronal health and gliosis.

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Figure 15

MRS (magnetic resonance spectroscopy) data from the Alzheimer's transgenic mouse brain, detecting metabolite ratios that reflect neuronal integrity and glial activation status.

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Figure 16

Correlation analysis between neuroinflammatory marker levels and metabolite concentrations in the APPswe x PS1de9 mouse model, suggesting mechanistic links between inflammation and metabolic disruption.

chart

Figure 17

Regional brain analysis comparing hippocampal and cortical neuroinflammatory profiles in the transgenic Alzheimer's model at an intermediate age time point.

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Figure 18

Longitudinal tracking of specific metabolite ratios (such as NAA/Cr or myo-inositol/Cr) in the Alzheimer's transgenic mouse model, used as biomarkers of neuronal health and gliosis.

chart

Figure 19

MRS (magnetic resonance spectroscopy) data from the Alzheimer's transgenic mouse brain, detecting metabolite ratios that reflect neuronal integrity and glial activation status.

chart

Figure 20

Correlation analysis between neuroinflammatory marker levels and metabolite concentrations in the APPswe x PS1de9 mouse model, suggesting mechanistic links between inflammation and metabolic disruption.

chart

Figure 21

Hippocampal tissue analysis from the APPswe x PS1de9 mouse model showing the relationship between amyloid deposition and local neuroinflammatory responses at a later disease stage.

micrograph

Figure 22

Quantitative comparison of inflammatory mediator expression between transgenic and wild-type mice at matched time points, highlighting the progressive nature of neuroinflammation in the Alzheimer's model.

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Figure 23

Western blot or protein expression analysis of key neuroinflammatory pathway components from brain homogenates of the Alzheimer's transgenic mice across the longitudinal study.

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Figure 24

Spatial distribution of neuroinflammatory markers in different brain regions of the APPswe x PS1de9 model, demonstrating region-specific vulnerability to Alzheimer's-related pathology.

micrograph

Figure 25

Hippocampal tissue analysis from the APPswe x PS1de9 mouse model showing the relationship between amyloid deposition and local neuroinflammatory responses at a later disease stage.

micrograph

Figure 26

Quantitative comparison of inflammatory mediator expression between transgenic and wild-type mice at matched time points, highlighting the progressive nature of neuroinflammation in the Alzheimer's model.

chart

Figure 27

Western blot or protein expression analysis of key neuroinflammatory pathway components from brain homogenates of the Alzheimer's transgenic mice across the longitudinal study.

chart

Figure 28

Spatial distribution of neuroinflammatory markers in different brain regions of the APPswe x PS1de9 model, demonstrating region-specific vulnerability to Alzheimer's-related pathology.

micrograph

Figure 29

Hippocampal tissue analysis from the APPswe x PS1de9 mouse model showing the relationship between amyloid deposition and local neuroinflammatory responses at a later disease stage.

micrograph

Figure 30

Quantitative comparison of inflammatory mediator expression between transgenic and wild-type mice at matched time points, highlighting the progressive nature of neuroinflammation in the Alzheimer's model.

chart

Figure 31

Western blot or protein expression analysis of key neuroinflammatory pathway components from brain homogenates of the Alzheimer's transgenic mice across the longitudinal study.

chart

Figure 32

Spatial distribution of neuroinflammatory markers in different brain regions of the APPswe x PS1de9 model, demonstrating region-specific vulnerability to Alzheimer's-related pathology.

micrograph

Figure 33

Late-stage metabolite profiling in the Alzheimer's transgenic mouse brain, showing pronounced neurochemical alterations compared to age-matched controls at the final time point.

chart

Figure 34

Multivariate statistical analysis of combined neuroinflammatory and metabolic data from the longitudinal APPswe x PS1de9 study, identifying key biomarker signatures that differentiate transgenic from wild-type animals.

chart

Figure 35

Summary heat map or correlation matrix integrating neuroinflammation and metabolite data across all time points in the Alzheimer's transgenic mouse model.

chart

Figure 36

Late-stage metabolite profiling in the Alzheimer's transgenic mouse brain, showing pronounced neurochemical alterations compared to age-matched controls at the final time point.

chart

Figure 37

Multivariate statistical analysis of combined neuroinflammatory and metabolic data from the longitudinal APPswe x PS1de9 study, identifying key biomarker signatures that differentiate transgenic from wild-type animals.

chart

Figure 38

Summary heat map or correlation matrix integrating neuroinflammation and metabolite data across all time points in the Alzheimer's transgenic mouse model.

chart

Figure 39

Late-stage metabolite profiling in the Alzheimer's transgenic mouse brain, showing pronounced neurochemical alterations compared to age-matched controls at the final time point.

chart

Figure 40

Multivariate statistical analysis of combined neuroinflammatory and metabolic data from the longitudinal APPswe x PS1de9 study, identifying key biomarker signatures that differentiate transgenic from wild-type animals.

chart

Figure 41

Summary heat map or correlation matrix integrating neuroinflammation and metabolite data across all time points in the Alzheimer's transgenic mouse model.

chart

Figure 42

Late-stage metabolite profiling in the Alzheimer's transgenic mouse brain, showing pronounced neurochemical alterations compared to age-matched controls at the final time point.

chart

Figure 43

Metabolite concentration profiles measured longitudinally in brain tissue of APPswe x PS1de9 transgenic Alzheimer's model mice. The data track neuroinflammatory and metabolic changes associated with disease progression.

chart

Figure 44

Metabolite concentration profiles measured longitudinally in brain tissue of APPswe x PS1de9 transgenic Alzheimer's model mice. The data track neuroinflammatory and metabolic changes associated with disease progression.

chart

Figure 45

Metabolite concentration profiles measured longitudinally in brain tissue of APPswe x PS1de9 transgenic Alzheimer's model mice. The data track neuroinflammatory and metabolic changes associated with disease progression.

chart

Figure 46

Longitudinal metabolite analysis in the APPswe x PS1de9 transgenic mouse model of Alzheimer's disease, comparing metabolite levels across different age groups. These profiles indicate progressive neuroinflammatory changes in affected brain regions.

chart

Figure 47

Longitudinal metabolite analysis in the APPswe x PS1de9 transgenic mouse model of Alzheimer's disease, comparing metabolite levels across different age groups. These profiles indicate progressive neuroinflammatory changes in affected brain regions.

chart

Figure 48

Longitudinal metabolite analysis in the APPswe x PS1de9 transgenic mouse model of Alzheimer's disease, comparing metabolite levels across different age groups. These profiles indicate progressive neuroinflammatory changes in affected brain regions.

chart

Figure 49

Longitudinal metabolite analysis in the APPswe x PS1de9 transgenic mouse model of Alzheimer's disease, comparing metabolite levels across different age groups. These profiles indicate progressive neuroinflammatory changes in affected brain regions.

chart

Figure 50

Longitudinal metabolite analysis in the APPswe x PS1de9 transgenic mouse model of Alzheimer's disease, comparing metabolite levels across different age groups. These profiles indicate progressive neuroinflammatory changes in affected brain regions.

chart

Figure 51

Longitudinal metabolite analysis in the APPswe x PS1de9 transgenic mouse model of Alzheimer's disease, comparing metabolite levels across different age groups. These profiles indicate progressive neuroinflammatory changes in affected brain regions.

chart

Figure 52

Longitudinal metabolite analysis in the APPswe x PS1de9 transgenic mouse model of Alzheimer's disease, comparing metabolite levels across different age groups. These profiles indicate progressive neuroinflammatory changes in affected brain regions.

chart

Figure 53

Longitudinal metabolite analysis in the APPswe x PS1de9 transgenic mouse model of Alzheimer's disease, comparing metabolite levels across different age groups. These profiles indicate progressive neuroinflammatory changes in affected brain regions.

chart

Figure 54

Longitudinal metabolite analysis in the APPswe x PS1de9 transgenic mouse model of Alzheimer's disease, comparing metabolite levels across different age groups. These profiles indicate progressive neuroinflammatory changes in affected brain regions.

chart

Figure 55

Longitudinal metabolite analysis in the APPswe x PS1de9 transgenic mouse model of Alzheimer's disease, comparing metabolite levels across different age groups. These profiles indicate progressive neuroinflammatory changes in affected brain regions.

chart

Figure 56

Quantitative metabolite profiling data from brain tissue of Alzheimer's disease model mice, illustrating how specific metabolite concentrations shift over time. The longitudinal design captures the trajectory of neuroinflammation-related metabolic alterations.

chart

Figure 57

Quantitative metabolite profiling data from brain tissue of Alzheimer's disease model mice, illustrating how specific metabolite concentrations shift over time. The longitudinal design captures the trajectory of neuroinflammation-related metabolic alterations.

chart

Figure 58

Quantitative metabolite profiling data from brain tissue of Alzheimer's disease model mice, illustrating how specific metabolite concentrations shift over time. The longitudinal design captures the trajectory of neuroinflammation-related metabolic alterations.

chart

Figure 59

Quantitative metabolite profiling data from brain tissue of Alzheimer's disease model mice, illustrating how specific metabolite concentrations shift over time. The longitudinal design captures the trajectory of neuroinflammation-related metabolic alterations.

chart

Figure 60

Quantitative metabolite profiling data from brain tissue of Alzheimer's disease model mice, illustrating how specific metabolite concentrations shift over time. The longitudinal design captures the trajectory of neuroinflammation-related metabolic alterations.

chart

Figure 61

Quantitative metabolite profiling data from brain tissue of Alzheimer's disease model mice, illustrating how specific metabolite concentrations shift over time. The longitudinal design captures the trajectory of neuroinflammation-related metabolic alterations.

chart

Figure 62

Quantitative metabolite profiling data from brain tissue of Alzheimer's disease model mice, illustrating how specific metabolite concentrations shift over time. The longitudinal design captures the trajectory of neuroinflammation-related metabolic alterations.

chart

Figure 63

Quantitative metabolite profiling data from brain tissue of Alzheimer's disease model mice, illustrating how specific metabolite concentrations shift over time. The longitudinal design captures the trajectory of neuroinflammation-related metabolic alterations.

chart

Figure 64

Quantitative metabolite profiling data from brain tissue of Alzheimer's disease model mice, illustrating how specific metabolite concentrations shift over time. The longitudinal design captures the trajectory of neuroinflammation-related metabolic alterations.

chart

Figure 65

Quantitative metabolite profiling data from brain tissue of Alzheimer's disease model mice, illustrating how specific metabolite concentrations shift over time. The longitudinal design captures the trajectory of neuroinflammation-related metabolic alterations.

chart

Figure 66

Brain metabolite measurements from APPswe x PS1de9 transgenic mice at multiple time points, providing evidence for progressive metabolic disruption linked to neuroinflammation. The data suggest region-specific vulnerability in this Alzheimer's disease model.

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Figure 67

Brain metabolite measurements from APPswe x PS1de9 transgenic mice at multiple time points, providing evidence for progressive metabolic disruption linked to neuroinflammation. The data suggest region-specific vulnerability in this Alzheimer's disease model.

chart

Figure 68

Brain metabolite measurements from APPswe x PS1de9 transgenic mice at multiple time points, providing evidence for progressive metabolic disruption linked to neuroinflammation. The data suggest region-specific vulnerability in this Alzheimer's disease model.

chart

Figure 69

Brain metabolite measurements from APPswe x PS1de9 transgenic mice at multiple time points, providing evidence for progressive metabolic disruption linked to neuroinflammation. The data suggest region-specific vulnerability in this Alzheimer's disease model.

chart

Figure 70

Brain metabolite measurements from APPswe x PS1de9 transgenic mice at multiple time points, providing evidence for progressive metabolic disruption linked to neuroinflammation. The data suggest region-specific vulnerability in this Alzheimer's disease model.

chart

Figure 71

Brain metabolite measurements from APPswe x PS1de9 transgenic mice at multiple time points, providing evidence for progressive metabolic disruption linked to neuroinflammation. The data suggest region-specific vulnerability in this Alzheimer's disease model.

chart

Figure 72

Brain metabolite measurements from APPswe x PS1de9 transgenic mice at multiple time points, providing evidence for progressive metabolic disruption linked to neuroinflammation. The data suggest region-specific vulnerability in this Alzheimer's disease model.

chart

Figure 73

Brain metabolite measurements from APPswe x PS1de9 transgenic mice at multiple time points, providing evidence for progressive metabolic disruption linked to neuroinflammation. The data suggest region-specific vulnerability in this Alzheimer's disease model.

chart

Figure 74

Brain metabolite measurements from APPswe x PS1de9 transgenic mice at multiple time points, providing evidence for progressive metabolic disruption linked to neuroinflammation. The data suggest region-specific vulnerability in this Alzheimer's disease model.

chart

Figure 75

Brain metabolite measurements from APPswe x PS1de9 transgenic mice at multiple time points, providing evidence for progressive metabolic disruption linked to neuroinflammation. The data suggest region-specific vulnerability in this Alzheimer's disease model.

chart

Figure 76

Longitudinal metabolite concentration data from the APPswe x PS1de9 Alzheimer's mouse model, revealing time-dependent changes in brain metabolic profiles. These measurements support the association between neuroinflammation and metabolic dysregulation.

chart

Figure 77

Longitudinal metabolite concentration data from the APPswe x PS1de9 Alzheimer's mouse model, revealing time-dependent changes in brain metabolic profiles. These measurements support the association between neuroinflammation and metabolic dysregulation.

chart

Figure 78

Longitudinal metabolite concentration data from the APPswe x PS1de9 Alzheimer's mouse model, revealing time-dependent changes in brain metabolic profiles. These measurements support the association between neuroinflammation and metabolic dysregulation.

chart

Figure 79

Longitudinal metabolite concentration data from the APPswe x PS1de9 Alzheimer's mouse model, revealing time-dependent changes in brain metabolic profiles. These measurements support the association between neuroinflammation and metabolic dysregulation.

chart

Figure 80

Longitudinal metabolite concentration data from the APPswe x PS1de9 Alzheimer's mouse model, revealing time-dependent changes in brain metabolic profiles. These measurements support the association between neuroinflammation and metabolic dysregulation.

chart

Figure 81

Longitudinal metabolite concentration data from the APPswe x PS1de9 Alzheimer's mouse model, revealing time-dependent changes in brain metabolic profiles. These measurements support the association between neuroinflammation and metabolic dysregulation.

chart

Figure 82

Longitudinal metabolite concentration data from the APPswe x PS1de9 Alzheimer's mouse model, revealing time-dependent changes in brain metabolic profiles. These measurements support the association between neuroinflammation and metabolic dysregulation.

chart

Figure 83

Longitudinal metabolite concentration data from the APPswe x PS1de9 Alzheimer's mouse model, revealing time-dependent changes in brain metabolic profiles. These measurements support the association between neuroinflammation and metabolic dysregulation.

chart

Figure 84

Longitudinal metabolite concentration data from the APPswe x PS1de9 Alzheimer's mouse model, revealing time-dependent changes in brain metabolic profiles. These measurements support the association between neuroinflammation and metabolic dysregulation.

chart

Figure 85

Longitudinal metabolite concentration data from the APPswe x PS1de9 Alzheimer's mouse model, revealing time-dependent changes in brain metabolic profiles. These measurements support the association between neuroinflammation and metabolic dysregulation.

chart

Figure 86

Supplementary metabolite profiling data from brain regions of APPswe x PS1de9 transgenic Alzheimer's mice. The extended longitudinal dataset captures the full trajectory of neuroinflammatory metabolic perturbations across the disease course.

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Figure 87

Supplementary metabolite profiling data from brain regions of APPswe x PS1de9 transgenic Alzheimer's mice. The extended longitudinal dataset captures the full trajectory of neuroinflammatory metabolic perturbations across the disease course.

chart

Figure 88

Supplementary metabolite profiling data from brain regions of APPswe x PS1de9 transgenic Alzheimer's mice. The extended longitudinal dataset captures the full trajectory of neuroinflammatory metabolic perturbations across the disease course.

chart

Figure 89

Supplementary metabolite profiling data from brain regions of APPswe x PS1de9 transgenic Alzheimer's mice. The extended longitudinal dataset captures the full trajectory of neuroinflammatory metabolic perturbations across the disease course.

chart

Figure 90

Supplementary metabolite profiling data from brain regions of APPswe x PS1de9 transgenic Alzheimer's mice. The extended longitudinal dataset captures the full trajectory of neuroinflammatory metabolic perturbations across the disease course.

chart

Figure 91

Supplementary metabolite profiling data from brain regions of APPswe x PS1de9 transgenic Alzheimer's mice. The extended longitudinal dataset captures the full trajectory of neuroinflammatory metabolic perturbations across the disease course.

chart

Figure 92

Supplementary metabolite profiling data from brain regions of APPswe x PS1de9 transgenic Alzheimer's mice. The extended longitudinal dataset captures the full trajectory of neuroinflammatory metabolic perturbations across the disease course.

chart

Figure 93

Supplementary metabolite profiling data from brain regions of APPswe x PS1de9 transgenic Alzheimer's mice. The extended longitudinal dataset captures the full trajectory of neuroinflammatory metabolic perturbations across the disease course.

chart

Figure 94

Supplementary metabolite profiling data from brain regions of APPswe x PS1de9 transgenic Alzheimer's mice. The extended longitudinal dataset captures the full trajectory of neuroinflammatory metabolic perturbations across the disease course.

chart

Figure 95

Supplementary metabolite profiling data from brain regions of APPswe x PS1de9 transgenic Alzheimer's mice. The extended longitudinal dataset captures the full trajectory of neuroinflammatory metabolic perturbations across the disease course.

chart

Figure 96

Supplementary metabolite profiling data from brain regions of APPswe x PS1de9 transgenic Alzheimer's mice. The extended longitudinal dataset captures the full trajectory of neuroinflammatory metabolic perturbations across the disease course.

chart

Figure 97

Supplementary metabolite profiling data from brain regions of APPswe x PS1de9 transgenic Alzheimer's mice. The extended longitudinal dataset captures the full trajectory of neuroinflammatory metabolic perturbations across the disease course.

chart

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