title: Susceptibility to diet-induced obesity and glucose intolerance in the APP (SWE)/PSEN1 (A246E) mouse model of Alzheimer's disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein.
abstract: OBJECTIVE
  Obesity is a major risk factor for development of insulin resistance, a proximal cause of type 2 diabetes and is also associated with an increased relative risk of Alzheimer's disease. We therefore investigated the susceptibility of transgenic mice carrying human mutated transgenes for amyloid precursor protein (APP (SWE)) and presenilin 1 (PSEN1 (A246E)) (APP/PSEN1), or PSEN1 (A246E) alone, which are well-characterised animal models of Alzheimer's disease, to develop obesity, glucose intolerance and insulin resistance, and whether this was age- and/or diet-dependent.
  
  
  METHODS
  We analysed the effects of age and/or diet on body weight of wild-type, PSEN1 and APP/PSEN1 mice. We also analysed the effects of diet on glucose homeostasis and insulin signalling in these mice.
  
  
  RESULTS
  While there were no body weight differences between 16-17- and 20-21-month-old PSEN1 mice, APP/PSEN1 mice and their wild-type controls on standard, low-fat, chow diet, the APP/PSEN1 mice still exhibited impaired glucose homeostasis, as investigated by glucose tolerance tests. This was associated with increased brain protein tyrosine phosphatase 1B protein levels in APP/PSEN1 mice. Interestingly, short-term high-fat diet (HFD) feeding of wild-type, PSEN1 and APP/PSEN1 mice for a period of 8 weeks led to higher body weight gain in APP/PSEN1 than in PSEN1 mice and wild-type controls. In addition, HFD-feeding caused fasting hyperglycaemia and worsening of glucose maintenance in PSEN1 mice, the former being further exacerbated in APP/PSEN1 mice. The mechanism(s) behind this glucose intolerance in PSEN1 and APP/PSEN1 mice appeared to involve increased levels of brain retinol-binding protein 4 and basal phosphorylation of S6 ribosomal protein, and decreased insulin-stimulated phosphorylation of Akt/protein kinase B and extracellular signal-regulated kinase 1/2 in the brain.
  
  
  CONCLUSIONS
  Our results indicate that Alzheimer's disease increases susceptibility to body weight gain induced by HFD, and to the associated glucose intolerance and insulin resistance.
authors.affiliation: Institute of Biological & Environmental Sciences, University of Aberdeen, Aberdeen, AB24 2TZ, Scotland, UK.
authors.forename: N
authors.initials: N
authors.lastname: Mody
authors.forename: A
authors.initials: A
authors.lastname: Agouni
authors.forename: G D
authors.initials: GD
authors.lastname: McIlroy
authors.forename: B
authors.initials: B
authors.lastname: Platt
authors.forename: M
authors.initials: M
authors.lastname: Delibegovic
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D018149:Glucose Intolerance / Q000503:physiopathology*; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000139:chemically induced / Q000378:metabolism*; D010766:Phosphorylation; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism*; D054839:Retinol-Binding Proteins, Plasma / Q000378:metabolism*; D038601:Ribosomal Protein S6 / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; C502487:Rbp4 protein, mouse; D054839:Retinol-Binding Proteins, Plasma; D038601:Ribosomal Protein S6; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1