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CNS and peripheral metabolomics of calorie restriction in a mouse model of Alzheimer’s disease (part I)

ABSTRACT: This pilot metabolomic study will evaluate brain specimens from an established mouse model of AD, the tq2576 mouse model of cerebral amyloid overexpression (APP), in comparison to their non-transgenic (NTG) littermates. These animals were either on a CR or ad libitum (AL) diet, and specimens were collected at two time points (5 and 15 months of age). Tissue from this cohorts of mice have already undergone microbiome analysis, and await coordinated brain and peripheral tissue assessments. Future analysis will include metabolomics, RNA-seq, and microarray data to assess the gut-brain microbiome system in neurodegenerative disorders.

ORGANISM(S): Mouse Mus Musculus

TISSUE(S): Brain

DISEASE(S): Alzheimers Disease

SUBMITTER: Susan Sumner

PROVIDER: ST000462 | MetabolomicsWorkbench | Wed Sep 07 00:00:00 BST 2016

REPOSITORIES: MetabolomicsWorkbench

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Project description:Immune cell infiltration to the brain is a prominent feature in aging and in various neurodegenerative diseases such as Alzheimer´s disease (AD). For example, a specific subpopulation of CD8+ T-cells clonally expands in the CSF of AD patients. Also, with AD progression that typically includes amyloid-beta plaque formation, neuronal damage and microglia-associated neuroinflammation, CD8+ T-cells infiltrate into the AD brain parenchyma and tightly associate with neuronal and microglia structures. The functional properties of CD8+ T-cells in the brain are largely unknown, besides the fact that experimental ablation in a transgenic AD animal model (APP-PS1) leads to changes in the expression of neuronal- and synapse-related genes. To gain further insights into the putative functional role of CD8+ T-cells in the brain, we explored and compared the transcriptomic profile of these cells in blood and brain of aged and transgenic AD mice. Surprisingly, CD8+ T-cells isolated from brains of aged APP-PS1 and WT animals had a similar transcriptomic profile, but they substantially differed from blood circulating CD8+ T-cells. The gene expression signature of brain CD8+ T-cells from APP-PS1 mice identified these cells as tissue-resident memory T-cells (Trm) indicated by specific regulation of genes such as Klf2/3, Ccr7, Sell, and Cxcr6. Immunohistochemical analysis confirmed the Trm identity of CD8+ T-cells at sites of amyloid-plaques. Gene ontology enrichment analysis on the significantly up-regulated genes showed an overrepresentation of biological processes as “response to virus”, “T-cell mediated immunity” and “response to interferon-beta” suggesting similarities to virus-responding T-cells. This is also supported by KEGG analysis, which highlighted upregulation of several pathways for “virus infections”, “cellular senescence” and “antigen processing and presentation”. In addition, the transcriptome of APP-PS1 brain CD8+ T-cells overlapped with gene microarray data of brain Trm CD8+ T-cells derived from an acute virus infection mouse model, suggesting similar functions of CD8+ T-cells in the brain either after viral infections or in AD. In conclusion, our herein presented data give new insights on the transcriptome of brain CD8+ T-cells and demonstrate adaptive immune responses in transgenic AD mice. This might open the door for immunotherapy as potential treatment option for AD.

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CNS and peripheral metabolomics of calorie restriction in a mouse model of Alzheimer’s disease (part I)

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