Neuronal human BACE1 knockin induces systemic diabetes in mice

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

Research output: Contribution to journalArticle

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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.
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 languageEnglish
JournalDiabetologia
DOIs
Publication statusPublished - 2 May 2016

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