title: The Effect of a High-Fat Diet on Brain Plasticity, Inflammation and Cognition in Female ApoE4-Knockin and ApoE-Knockout Mice.
abstract: 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.
authors.affiliation: Department of Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Carola I F
authors.initials: CI
authors.lastname: Janssen
authors.affiliation: Department of Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Diane
authors.initials: D
authors.lastname: Jansen
authors.affiliation: Department of Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Martina P C
authors.initials: MP
authors.lastname: Mutsaers
authors.affiliation: Department of Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Pieter J W C
authors.initials: PJ
authors.lastname: Dederen
authors.affiliation: Department of Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Bram
authors.initials: B
authors.lastname: Geenen
authors.affiliation: Department of Internal Medicine, Laboratory of Vascular Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Monique T
authors.initials: MT
authors.lastname: Mulder
authors.affiliation: Department of Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Kiliaan
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000172:deficiency* / Q000378:metabolism; D001835:Body Weight; D001921:Brain / Q000473:pathology* / Q000503:physiopathology*; D003071:Cognition / Q000502:physiology*; D018891:Dentate Gyrus / Q000378:metabolism; D059305:Diet, High-Fat; D000076122:Disks Large Homolog 4 Protein; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005260:Female; D055879:Gene Knock-In Techniques; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051528:Guanylate Kinases / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology*; D018782:Maze Learning; D008565:Membrane Proteins / Q000378:metabolism; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009473:Neuronal Plasticity; D009479:Neuropeptides / Q000378:metabolism; D009929:Organ Size; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D053327:Apolipoprotein E4; D000076122:Disks Large Homolog 4 Protein; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D051272:Glucose Transporter Type 1; D051528:Guanylate Kinases; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C000714328:DCX protein, human; C000714847:Dcx protein, mouse; C501447:Dlg4 protein, mouse; C495678:Slc2a1 protein, mouse