Abstract
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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-3960-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Highlights
The incidence of type 2 diabetes and Alzheimer’s disease is rising at an alarming rate
Systemic glucose homeostasis is impaired in PLB4 mice We first confirmed that human BACE1 expression was brain specific (Fig. 1a,b) and established that body weights were normal in PLB4 mice aged up to 4 months (Fig. 1c) but decreased compared with wild-type (WT) controls at 5 and 8 months
Abnormal neuronal insulin signalling Since hBACE1 was expression was forebrain specific, we investigated whether neuronal insulin signalling was affected in a b symptomatic PLB4 mice by probing for markers of the insulin IR–Akt–GSK-3β transduction pathway (Fig. 4) in forebrain lysates of 8-month-old fasted mice
Summary
The incidence of type 2 diabetes and Alzheimer’s disease is rising at an alarming rate. Type 2 diabetes increases the risk of Alzheimer’s disease [1]; systemic glucose intolerance and insulin resistance are reported in dementia patients without a history of diabetes [2]. Brain BACE1 levels increase with age [8], in Alzheimer’s disease [9], and following pathological events [10, 11]. We recently confirmed that neuronspecific knockin of human (h)BACE1 induces Aβ accumulation, promotes brain inflammation and recapitulates Alzheimer’s disease-like phenotypes in mice in the absence of mutant APP expression [13], suggesting that BACE1 represents a molecular risk factor for sporadic Alzheimer’s disease
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