title: Reversal of high fat diet-induced obesity improves glucose tolerance, inflammatory response, β-amyloid accumulation and cognitive decline in the APP/PSEN1 mouse model of Alzheimer's disease.
abstract: This study assessed the extent to which high fat diet (HFD)-induced β-amyloid accumulation and cognitive decline in APP/PSEN1 mice are reversible through control of fat intake. Ten months of HFD (60% calories from fat) led to significant deficits in a 2-trial Y maze task, and nest building assay, and decreased voluntary locomotor activity. The HFD induced an inflammatory response, indicated by increased expression of several inflammatory markers. Substituting a low fat diet led to pronounced weight loss and correction of glucose intolerance, decreases in the inflammatory response, and improved performance on behavioral tasks in both wild-type and APP/PSEN1 transgenic mice. Insoluble β-amyloid levels, and extent of tau phosphorylation were also lower following dietary reversal in APP/PSEN1 mice compared to high fat-fed animals, indicating that the inflammatory response may have contributed to key pathogenic pathways in the Alzheimer's disease model. The data suggest that weight loss can be a vital strategy for cognitive protection, but also highlight potential mechanisms for intervention when sustained weight loss is not possible.
authors.affiliation: Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Vanderbilt University Medical Center, 2213 Garland Ave., Nashville, TN 37232, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Walker
authors.affiliation: Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Vanderbilt University Medical Center, 2213 Garland Ave., Nashville, TN 37232, USA.
authors.forename: Shilpy
authors.initials: S
authors.lastname: Dixit
authors.affiliation: Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Vanderbilt University Medical Center, 2213 Garland Ave., Nashville, TN 37232, USA.
authors.forename: Anjelica C
authors.initials: AC
authors.lastname: Saulsberry
authors.affiliation: Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Vanderbilt University Medical Center, 2213 Garland Ave., Nashville, TN 37232, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: May
authors.affiliation: Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Vanderbilt University Medical Center, 2213 Garland Ave., Nashville, TN 37232, USA. Electronic address: fiona.harrison@vanderbilt.edu.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Harrison
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D060825:Cognitive Dysfunction / Q000150:complications*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005260:Female; D005947:Glucose / Q000378:metabolism*; D008297:Male; D008569:Memory Disorders / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009765:Obesity / Q000150:complications* / Q000378:metabolism; D053764:Presenilin-1 / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; C580804:presenilin 1, mouse; D005947:Glucose
keywords: Behavior; Cognition; Inflammatory response, β-amyloid, high fat diet; Obesity