title: Neuronal human BACE1 knockin induces systemic diabetes in mice.
abstract: β-Secretase 1 (BACE1) is a key enzyme in Alzheimer's disease pathogenesis that catalyses the amyloidogenic cleavage of amyloid precursor protein (APP). Recently, global Bace1 deletion was shown to protect against diet-induced obesity and diabetes, suggesting that BACE1 is a potential regulator of glucose homeostasis. Here, we investigated whether increased neuronal BACE1 is sufficient to alter systemic glucose metabolism, using a neuron-specific human BACE1 knockin mouse model (PLB4).
  
  
  
  Glucose homeostasis and adiposity were determined by glucose tolerance tests and EchoMRI, lipid species were measured by quantitative lipidomics, and biochemical and molecular alterations were assessed by western blotting, quantitative PCR and ELISAs. Glucose uptake in the brain and upper body was measured via (18)FDG-PET imaging.
  
  
  
  Physiological and molecular analyses demonstrated that centrally expressed human BACE1 induced systemic glucose intolerance in mice from 4 months of age onward, alongside a fatty liver phenotype and impaired hepatic glycogen storage. This diabetic phenotype was associated with hypothalamic pathology, i.e. deregulation of the melanocortin system, and advanced endoplasmic reticulum (ER) stress indicated by elevated central C/EBP homologous protein (CHOP) signalling and hyperphosphorylation of its regulator eukaryotic translation initiation factor 2α (eIF2α). In vivo (18)FDG-PET imaging further confirmed brain glucose hypometabolism in these mice; this corresponded with altered neuronal insulin-related signalling, enhanced protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4) levels, along with upregulation of the ribosomal protein and lipid translation machinery. Increased forebrain and plasma lipid accumulation (i.e. ceramides, triacylglycerols, phospholipids) was identified via lipidomics analysis.
  
  
  
  Our data reveal that neuronal BACE1 is a key regulator of metabolic homeostasis and provide a potential mechanism for the high prevalence of metabolic disturbance in Alzheimer's disease.
authors.affiliation: School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK.
authors.forename: Kaja
authors.initials: K
authors.lastname: Plucińska
authors.affiliation: School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK.
authors.forename: Ruta
authors.initials: R
authors.lastname: Dekeryte
authors.affiliation: School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK.
authors.forename: David
authors.initials: D
authors.lastname: Koss
authors.affiliation: School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK.
authors.forename: Kirsty
authors.initials: K
authors.lastname: Shearer
authors.affiliation: School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK.
authors.forename: Nimesh
authors.initials: N
authors.lastname: Mody
authors.affiliation: Department of Diabetes and Cardiovascular Science, Centre for Health Science, University of the Highlands and Islands, Inverness, Scotland, UK.
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Whitfield
authors.affiliation: Department of Diabetes and Cardiovascular Science, Centre for Health Science, University of the Highlands and Islands, Inverness, Scotland, UK.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Doherty
authors.affiliation: School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK.
authors.forename: Marco
authors.initials: M
authors.lastname: Mingarelli
authors.affiliation: School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK.
authors.forename: Andy
authors.initials: A
authors.lastname: Welch
authors.affiliation: School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK.
authors.forename: Gernot
authors.initials: G
authors.lastname: Riedel
authors.affiliation: School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK. m.delibegovic@abdn.ac.uk.
authors.forename: Mirela
authors.initials: M
authors.lastname: Delibegovic
authors.affiliation: School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK. b.platt@abdn.ac.uk.
authors.forename: Bettina
authors.initials: B
authors.lastname: Platt
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000378:metabolism / Q000503:physiopathology; D006706:Homeostasis; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; D005947:Glucose
keywords: 18FDG-PET; Ceramide; ER stress; Glucose homeostasis; Insulin signalling; Neuronal BACE1