The Effect of a High-Fat Diet on Brain Plasticity, Inflammation and Cognition in Female ApoE4-Knockin and ApoE-Knockout Mice

PLoS One. 2016 May 12;11(5):e0155307. doi: 10.1371/journal.pone.0155307. eCollection 2016.


Apolipoprotein E4 (ApoE4), one of three common isoforms of ApoE, is a major risk factor for late-onset Alzheimer disease (AD). ApoE-deficient mice, as well as mice expressing human ApoE4, display impaired learning and memory functions and signs of neurodegeneration. Moreover, ApoE protects against high-fat (HF) diet induced neurodegeneration by its role in the maintenance of the integrity of the blood-brain barrier. The influence of a HF diet on the progression of AD-like cognitive and neuropathological changes was assessed in wild-type (WT), human ApoE4 and ApoE-knockout (ApoE-/-) mice to evaluate the modulatory role of ApoE in this process. From 12 months of age, female WT, ApoE4, and ApoE-/- mice were fed either a standard or a HF diet (19% butter, 0.5% cholate, 1.25% cholesterol) throughout life. At 15 months of age mice performed the Morris water maze, evaluating spatial learning and memory. ApoE-/- showed increased spatial learning compared to WT mice (p = 0.009). HF diet improved spatial learning in WT mice (p = 0.045), but did not affect ApoE4 and ApoE-/- mice. Immunohistochemical analyses of the hippocampus demonstrated increased neuroinflammation (CD68) in the cornu ammonis 1 (CA1) region in ApoE4 (p = 0.001) and in ApoE-/- (p = 0.032) mice on standard diet. HF diet tended to increase CD68 in the CA1 in WT mice (p = 0.052), while it decreased in ApoE4 (p = 0.009), but ApoE-/- remained unaffected. A trend towards increased neurogenesis (DCX) was found in both ApoE4 (p = 0.052) and ApoE-/- mice (p = 0.068). In conclusion, these data suggest that HF intake induces different effects in WT mice compared to ApoE4 and ApoE-/- with respect to markers for cognition and neurodegeneration. We propose that HF intake inhibits the compensatory mechanisms of neuroinflammation and neurogenesis in aged female ApoE4 and ApoE-/- mice.

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Apolipoprotein E4 / deficiency*
  • Apolipoprotein E4 / metabolism
  • Body Weight
  • Brain / pathology*
  • Brain / physiopathology*
  • Cognition / physiology*
  • Dentate Gyrus / metabolism
  • Diet, High-Fat
  • Disks Large Homolog 4 Protein
  • Doublecortin Domain Proteins
  • Doublecortin Protein
  • Female
  • Gene Knock-In Techniques
  • Glucose Transporter Type 1 / metabolism
  • Guanylate Kinases / metabolism
  • Humans
  • Immunohistochemistry
  • Inflammation / pathology*
  • Maze Learning
  • Membrane Proteins / metabolism
  • Mice, Knockout
  • Microtubule-Associated Proteins / metabolism
  • Neuronal Plasticity*
  • Neuropeptides / metabolism
  • Organ Size


  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • Apolipoprotein E4
  • CD68 antigen, human
  • DCX protein, human
  • Dcx protein, mouse
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Doublecortin Domain Proteins
  • Doublecortin Protein
  • Glucose Transporter Type 1
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Neuropeptides
  • Slc2a1 protein, mouse
  • Guanylate Kinases

Grants and funding

The authors have no support or funding to report.