Neuronal human BACE1 knockin induces systemic diabetes in mice

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.

Amyloid precursor protein in pancreatic islets

“…This time point was important for assessing the role of islet APP in glucose tolerance because it is well before Aβ deposits are known to form in the CNS of the APP/PS1 mouse. Aβ oligomers or over-overexpression of the Aβ producing enzyme BACE1 in the brain have recently been demonstrated as sufficient to induce peripheral metabolic dysregulation (Clarke, et al 2015; Plucinska, et al 2016). We detected no significant differences in glucose tolerance across strain, indicating ablation or overexpression of mutant APP does not severely compromise glucose homeostasis mechanisms or severely impair islet function at two months of age.…”

Decay in Retinoic Acid Signaling in Varied Models of Alzheimer’s Disease and In-Vitro Test of Novel Retinoic Acid Receptor Ligands (RAR-Ms) to Regulate Protective Genes

“…RBP4 is a liver secreted retinol carrier protein in the circulation [82]. Its function in the brain is unknown but an increase in RBP4 protein levels was reported in the brain of APP/PSEN1 AD model mice [83], and it is upregulated in the liver and forebrain of 8-monthold PLB4 mice [84]. The current study reproduced these findings and Rbp4 gene levels were upregulated in the brains of all 6-month-old PLB models but at 3 months only in the PLB1 Double mouse line.…”

The therapeutic potential of metabolic hormones in the treatment of age-related cognitive decline and Alzheimer's disease

“…Global knockout of β-secretase 1, a key enzyme involved in Aβ production, has been shown to protect against diet-induced obesity and diabetes [161]. Furthermore, β-secretase 1 expression exclusively in the CNS facilitates hypothalamic dysfunction, impaired glucose tolerance, and glycogen storage, as well as a fatty liver phenotype [162]. To this end, further investigation is warranted to discern the exact nature of the relationship between AD and metabolic dysfunction.…”