Prolonged diet induced obesity has minimal effects towards brain pathology in mouse model of cerebral amyloid angiopathy: Implications for studying obesity-brain interactions in mice

Le Zhang, Kalavathi Dasuri, Sun Ok Fernandez-Kim, Annadora J. Bruce-Keller, Linnea R. Freeman, Jennifer K. Pepping, Tina L. Beckett, M. Paul Murphy, Jeffrey N. Keller

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Cerebral amyloid angiopathy (CAA) occurs in nearly every individual with Alzheimer's disease (AD) and Down's syndrome, and is the second largest cause of intracerebral hemorrhage. Mouse models of CAA have demonstrated evidence for increased gliosis contributing to CAA pathology. Nearly two thirds of Americans are overweight or obese, with little known about the effects of obesity on the brain, although increasingly the vasculature appears to be a principle target of obesity effects on the brain. In the current study we describe for the first time whether diet induced obesity (DIO) modulates glial reactivity, amyloid levels, and inflammatory signaling in a mouse model of CAA. In these studies we identify surprisingly that DIO does not significantly increase Aβ levels, astrocyte (GFAP) or microglial (IBA-1) gliosis in the CAA mice. However, within the hippocampal gyri a localized increase in reactive microglia were increased in the CA1 and stratum oriens relative to CAA mice on a control diet. DIO was observed to selectively increase IL-6 in CAA mice, with IL-1β and TNF-α not increased in CAA mice in response to DIO. Taken together, these data show that prolonged DIO has only modest effects towards Aβ in a mouse model of CAA, but appears to elevate some localized microglial reactivity within the hippocampal gyri and selective markers of inflammatory signaling. These data are consistent with the majority of the existing literature in other models of Aβ pathology, which surprisingly show a mixed profile of DIO effects towards pathological processes in mouse models of neurodegenerative disease. The importance for considering the potential impact of ceiling effects in pathology within mouse models of Aβ pathogenesis, and the current experimental limitations for DIO in mice to fully replicate metabolic dysfunction present in human obesity, are discussed. This article is part of a Special Issue entitled: Animal Models of Disease.

Original languageEnglish
Pages (from-to)1456-1462
Number of pages7
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1832
Issue number9
DOIs
StatePublished - Sep 2013

Bibliographical note

Funding Information:
This work utilized the facilities of the Cell Biology and Bioimaging Core that are supported in part by COBRE (NIH 2P20-RR021945) and NORC (NIH 2P30-DK072476) center grants from the National Institutes of Health, the Pennington Animal Metabolism and Behavior Core. The work was supported by funds from the NIH and Hibernia National Bank/Edward G Schleider Chair to JNK. The authors also thank Dr William Van Nostrand for supplying original founder CAA mice used for the generation of mice in the current study.

Keywords

  • Adiposity
  • Alzheimer's disease
  • Astrocyte
  • Diabetes
  • Inflammation
  • Microglia

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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