Neuronal human BACE1 knock-in induces systemic diabetes in mice

Kaja Plucinska; Ruta Dekeryte; David Koss; Kirsty Shearer; Nimesh Mody; Phillip D. Whitfield; Mary K. Doherty; Marco Mingarelli; Andy Welch; Gernot Riedel; Mirela Delibegovic; Bettina Platt

doi:10.1007/s00125-016-3960-1

Neuronal human BACE1 knock-in induces systemic diabetes in mice

Kaja Plucinska, Ruta Dekeryte, David Koss, Kirsty Shearer, Nimesh Mody, Phillip D. Whitfield, Mary K. Doherty, Marco Mingarelli, Andy Welch, Gernot Riedel, Mirela Delibegovic, Bettina Platt

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Abstract

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 18FDG-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 18FDG-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.

Original language	English
Pages (from-to)	1513-1523
Number of pages	11
Journal	Diabetologia
Volume	59
Issue number	7
Early online date	2 May 2016
DOIs	https://doi.org/10.1007/s00125-016-3960-1
Publication status	Published - Jul 2016

Keywords

neuronal BACE1
glucose homeostasis
ceramide
ER stress
18FDG-PET
insulin signalling

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Neuronal human BACE1 knockin induces systemic diabetes in mice
© The Author(s) 2016 This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Final published version, 1.42 MBLicence: CC BY
Plucinska-et-al-Diabetologia-neuronal-human-vor
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http:// creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Final published version, 1.42 MBLicence: CC BY

Mirela Delibegovic
- School of Medicine, Medical Sciences & Nutrition, Medical Sciences - Professor in Diabetes Physiology and Signalling
- Institute of Medical Sciences
Person: Academic
Bettina Platt, PhD, FSB
- School of Medicine, Medical Sciences & Nutrition, Medical Sciences - Chair in Translational Neuroscience
- Institute of Medical Sciences
Person: Academic
Gernot Riedel
- School of Medicine, Medical Sciences & Nutrition, Medical Sciences - Personal Chair
- Institute of Medical Sciences
Person: Academic

Cite this

@article{075ba40207854123bcc881afc56f3750,

title = "Neuronal human BACE1 knock-in induces systemic diabetes in mice",

abstract = "Aimsβ-Secretase 1 (BACE1) is a key enzyme in Alzheimer{\textquoteright}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).MethodsGlucose 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 18FDG-PET imaging.ResultsPhysiological 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 18FDG-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/interpretationOur 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{\textquoteright}s disease.",

keywords = "neuronal BACE1, glucose homeostasis, ceramide, ER stress, 18FDG-PET, insulin signalling ",

author = "Kaja Plucinska and Ruta Dekeryte and David Koss and Kirsty Shearer and Nimesh Mody and Whitfield, {Phillip D.} and Doherty, {Mary K.} and Marco Mingarelli and Andy Welch and Gernot Riedel and Mirela Delibegovic and Bettina Platt",

note = "Acknowledgements The authors thank S. Tammireddy (Diabetes and Cardiovascular Science, University of the Highlands and Islands, Inverness, UK) for technical support with the lipidomics component. Funding We would like to thank R. Simcox, Romex Oilfield Chemicals, for financial support for KP, and acknowledge additional contributions from the Scottish Alzheimer{\textquoteright}s Research UK network for the lipidomics work. The College of Life Science and Medicine, University of Aberdeen, sponsored the imaging study. MD was funded by British Heart Foundation and Diabetes UK; NM was funded by a British Heart Foundation Intermediate Fellowship; KS was funded by a European Foundation for the Study of Diabetes/Lilly programme grant; and RD was funded by an Institute of Medical Sciences PhD studentship.",

year = "2016",

month = jul,

doi = "10.1007/s00125-016-3960-1",

language = "English",

volume = "59",

pages = "1513--1523",

journal = "Diabetologia",

issn = "0012-186X",

publisher = "Springer ",

number = "7",

}

TY - JOUR

T1 - Neuronal human BACE1 knock-in induces systemic diabetes in mice

AU - Plucinska, 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

N1 - Acknowledgements The authors thank S. Tammireddy (Diabetes and Cardiovascular Science, University of the Highlands and Islands, Inverness, UK) for technical support with the lipidomics component. Funding We would like to thank R. Simcox, Romex Oilfield Chemicals, for financial support for KP, and acknowledge additional contributions from the Scottish Alzheimer’s Research UK network for the lipidomics work. The College of Life Science and Medicine, University of Aberdeen, sponsored the imaging study. MD was funded by British Heart Foundation and Diabetes UK; NM was funded by a British Heart Foundation Intermediate Fellowship; KS was funded by a European Foundation for the Study of Diabetes/Lilly programme grant; and RD was funded by an Institute of Medical Sciences PhD studentship.

PY - 2016/7

Y1 - 2016/7

N2 - Aimsβ-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).MethodsGlucose 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 18FDG-PET imaging.ResultsPhysiological 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 18FDG-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/interpretationOur 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 - Aimsβ-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).MethodsGlucose 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 18FDG-PET imaging.ResultsPhysiological 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 18FDG-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/interpretationOur 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 - neuronal BACE1

KW - glucose homeostasis

KW - ceramide

KW - ER stress

KW - 18FDG-PET

KW - insulin signalling

U2 - 10.1007/s00125-016-3960-1

DO - 10.1007/s00125-016-3960-1

M3 - Article

C2 - 27138913

VL - 59

SP - 1513

EP - 1523

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 7

ER -

Neuronal human BACE1 knock-in induces systemic diabetes in mice

Abstract

Keywords

UN SDGs

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Mirela Delibegovic

Bettina Platt, PhD, FSB

Gernot Riedel

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