Neuronal human BACE1 knockin induces systemic diabetes in mice

TY - JOUR

T1 - Neuronal human BACE1 knockin induces systemic diabetes in mice

AU - Plucińska, Kaja

AU - Dekeryte, Ruta

AU - Koss, David

AU - Shearer, Kirsty

AU - Mody, Nimesh

AU - Whitfield, Phillip D

AU - Doherty, Mary K

AU - Mingarelli, Marco

AU - Welch, Andy

AU - Riedel, Gernot

AU - Delibegovic, Mirela

AU - Platt, Bettina

PY - 2016/7/1

Y1 - 2016/7/1

N2 - AIMS: 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).METHODS: 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.RESULTS: 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.CONCLUSIONS/INTERPRETATION: 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.

AB - AIMS: 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).METHODS: 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.RESULTS: 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.CONCLUSIONS/INTERPRETATION: 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.

KW - Alzheimer Disease/genetics

KW - Amyloid Precursor Protein Secretases/genetics

KW - Amyloid beta-Protein Precursor/genetics

KW - Animals

KW - Aspartic Acid Endopeptidases/genetics

KW - Diabetes Mellitus/genetics

KW - Disease Models, Animal

KW - Glucose/metabolism

KW - Glucose Intolerance/metabolism

KW - Homeostasis

KW - Humans

KW - Mice

KW - Neurons/metabolism

KW - Obesity/genetics

KW - Protein Tyrosine Phosphatase, Non-Receptor Type 1/genetics

U2 - 10.1007/s00125-016-3960-1

DO - 10.1007/s00125-016-3960-1

M3 - Journal article

C2 - 27138913

SN - 0012-186X

VL - 59

SP - 1513

EP - 1523

JO - Diabetologia

JF - Diabetologia

IS - 7

ER -