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Longitudinal investigation of neuroinflammation and metabolite profiles in the APPswe ×PS1?e9 transgenic mouse model of Alzheimer's disease.

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 ×PS1?e9 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.

SUBMITTER: Chaney A

PROVIDER: S-EPMC5846890 | biostudies-other | 2018 Feb

REPOSITORIES: biostudies-other

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

Chaney Aisling A Bauer Martin M Bochicchio Daniela D Smigova Alison A Kassiou Michael M Davies Karen E KE Williams Steve R SR Boutin Herve H

Journal of neurochemistry 20171215 3

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 we ...[more]

PMID: 29124761

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Project description:Neuroinflammation, characterized by chronic activation of the myeloid-derived microglia, is a hallmark of Alzheimer's disease (AD). Systemic inflammation, typically resulting from infection, has been linked to the progression of AD due to exacerbation of the chronic microglial reaction. However, the mechanism and the consequences of this exacerbation are largely unknown. Here, we mimicked systemic inflammation in AD with weekly intraperitoneal (i.p.) injections of APPSWE/PS1?E9 transgenic mice with E. coli lipopolysaccharide (LPS) from 9 to 12 months of age, corresponding to the period with the steepest increase in amyloid pathology. We found that the repeated LPS injections ameliorated amyloid pathology in the neocortex while increasing the neuroinflammatory reaction. To elucidate mechanisms, we analyzed the proteome of the hippocampus from the same mice as well as in unique samples of CNS myeloid cells. The repeated LPS injections stimulated protein pathways of the complement system, retinoid receptor activation and oxidative stress. CNS myeloid cells from transgenic mice showed enrichment in pathways of amyloid-beta clearance and elevated levels of the lysosomal protease cathepsin Z, as well as amyloid precursor protein, apolipoprotein E and clusterin. These proteins were found elevated in the proteome of both LPS and vehicle injected transgenics, and co-localized to CD11b+ microglia in transgenic mice and in primary murine microglia. Additionally, cathepsin Z, amyloid precursor protein, and apolipoprotein E appeared associated with amyloid plaques in neocortex of AD cases. Interestingly, cathepsin Z was expressed in microglial-like cells and co-localized to CD68+ microglial lysosomes in AD cases, and it was expressed in perivascular cells in AD and control cases. Taken together, our results implicate systemic LPS administration in ameliorating amyloid pathology in early-to-mid stage disease in the APPSWE/PS1?E9 mouse and attract attention to the potential disease involvement of cathepsin Z expressed in CNS myeloid cells in AD.

Project description:BackgroundA great body of evidence suggests that there are retinal functional and structural changes that occur in Alzheimer's disease (AD). However, whether such changes are primary or secondary remains to be elucidated. We studied a range of retinal functional and structural parameters in association with AD- specific pathophysiological markers in the double transgenic APP/PS1 and control mice across age.MethodsElectroretinogram (ERG) and optical coherence tomography (OCT) was performed in APP/PS1 and wild type (WT) control mice every 3 months from 3 to 12?months of age. For functional assessment, the a- and b-wave of the ERG, amplitude of oscillatory potentials (OP) and the positive scotopic threshold response (pSTR) were quantified at each time point. For structural assessment, the inner and outer retinal thickness was segmented and measured from OCT scans. Episodic memory was evaluated at 6, 9 and 12?months of age using the novel object recognition test. Amyloid beta (A?) distribution in the hippocampus and the retina were visualised at 3, 6 and 12?months of age. Inter- and intra- group analysis was performed to study rate of change for each parameter between the two groups.ResultsInter-group analysis revealed a significant difference in b-wave and OPs of APP/PS1 compared to WT controls starting from 3?months (p?<?0.001). There was also a significant difference in the amplitude of pSTR between the two groups starting from 6?months (p?<?0.001). Furthermore, a significant difference in the inner retinal thickness, between the two groups, was observed starting from 9?months (p?<?0.001).ConclusionsWe observed an age-related decline in retinal functional and structural parameters in both APP/PS1 and WT controls, however, inter-group analysis revealed that inner retinal functional and structural decline is exacerbated in APP/PS1 mice, and that retinal functional changes precede structural changes in this strain. Further studies are required to confirm whether such phenomenon occurs in humans and if studying retinal functional changes can aid-in early assessment of AD.

Dataset Information

Longitudinal investigation of neuroinflammation and metabolite profiles in the APPswe ×PS1?e9 transgenic mouse model of Alzheimer's disease.

Publications

Longitudinal investigation of neuroinflammation and metabolite profiles in the APP<sub>swe</sub> ×PS1<sub>Δe9</sub> transgenic mouse model of Alzheimer's disease.

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