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

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.

Fig. 1. Body weights and body fat following diet induced obesity

(A) Control HFD mice (C-HFD) were significantly heavier than all other groups (p<0.05) while CAA control diet (CAA-CD) mice weighed significantly less than all other groups (p<0.05). (B) Body fat as measured by NMR revealed increased total body fat (p<0.05) for both groups fed the HFD. The CAA-CD mice had less fat compared to all other groups (p<0.05).

Fig. 2. Effects of the diet induced obesity on the gross inflammatory signaling pathway in mouse brains

The mRNA level of TNF-α (A), IL-1 (B) and IL-6 (C) in different mouse brain was examined. HFD exposure selectively increased IL-6 in CAA mice (p<0.05).

Fig. 3. Effects of the diet induced obesity on astrocyte and microglial reactivity

Diet induced obesity did not significantly alter the gross protein levels of either astrocyte (GFAP) or microglial (IBA-1) reactivity.

Fig. 4. Diet induced obesity did not significantly alter immunoreactivity and distribution of GFAP in the hippocampus of CAA mice

The levels of astrocyte reactivity were measured in the brain using GFAP immunoreactivity (purple) and co-localized with cerebral blood vessels using collagen IV immunoreactivity (brown).

Fig. 5. Effects of diet induced obesity on the immuoreactivity and distribution of IBA1 in the hippocampus of CAA mice

The levels of microglial reactivity were measured in the brain using IBA-1 immunoreactivity (purple) and co-localized with cerebral blood vessels using collagen IV immunoreactivity (brown).