BACE cleavage of APP does not drive the diabetic phenotype of PLB4 mice

Alzheimer's Disease (AD) and Type 2 Diabetes Mellitus (T2DM), two prevalent diseases related to ageing, often share common pathologies including increased inflammation, endoplasmic reticulum (ER) stress, and impaired metabolic homeostasis predominantly affecting different organs. Therefore, it was unexpected to find in a previous study that neuronal hBACE1 knock-in (PLB4 mouse) leads to both an AD- and T2DM- like phenotype. The complexity of this co-morbidity phenotype required a deeper systems approach to explore the age-related changes in AD and T2DM-like pathologies of the PLB4 mouse. Therefore, we here analysed key neuronal and metabolic tissues comparing associated pathologies to those of normal ageing.

Glucose tolerance, insulin sensitivity and protein turnover were assessed in 5-h fasted 3- and 8-month-old male PLB4 and wild-type mice. Western Blot and quantitative PCR were performed to determine regulation of homeostatic and metabolic pathways in insulin-stimulated brain, liver and muscle tissue.

Neuronal hBACE1 expression caused early pathological cleavage of APP (increased monomeric Aβ (mAβ) levels at 3 months), in parallel with brain ER stress (increased phosphorylation of the translation regulation factor (p-eIF2α) and the chaperone binding immunoglobulin protein (BIP)). However, APP processing shifted over time (higher full-length APP and secreted APPβ levels, alongside lower mAβ and secreted APPα at 8 months), together with increased ER stress (phosphorylated/total inositol-requiring enzyme 1α (IRE1α)) in brain and liver. Metabolically, systemic glucose intolerance was evident from 3 months, yet metabolic signalling varied greatly between tissues and ages, and was confined to the periphery (increased muscle insulin receptors (IR), dipeptidyl-peptidase-4 (DPP4) levels, and decreased phosphorylated protein Kinase B (p-Akt), alongside increased liver DPP4 and fibroblast growth factor 21 (FGF21)), all of which normalised to wild-type levels at 8 months.

Our data suggest that the murine nervous system is affected early by APP misprocessing as a result of hBACE1 introduction, which coincided with ER stress, but not IR changes, and was alleviated with age. Peripheral metabolic alterations occurred early and revealed tissue-specific (liver vs. muscle) adaptations in metabolic markers but did not correlate with neuronal APP processing. Compensatory vs. contributory neuronal mechanisms associated with hBACE1 expression at different ages may explain why mice intrinsically do not develop AD pathologies and may offer new insights for future interventions.