Changes in metabolic signalling in a mouse model of Alzheimer's disease (360G-Wellcome-207236_Z_17_Z)

The protease, BACE1 (beta-site amyloid precursor protein (APP)-cleaving enzyme 1) is rate-limiting in amyloid beta (Ab) production. Ab peptides are prone to aggregation causing amyloid plaques, a process strongly linked to Alzheimer’s disease (AD). People with AD have an increased risk of T2D (Janson et al., 2004) and people with peripheral insulin resistance correlate with AD risk (Li & Hölscher 2007). Central obesity also increases dementia risk, independently of diabetes (Luchsinger 2010). Thus, the pathological processes underlying AD are linked with the metabolic disturbances associated with T2D and obesity. We hypothesise that raised BACE1 activity driven by high fat feeding results in the induction of central insulin and leptin resistance and disordered glucose and lipid metabolism, increasing susceptibility to diabetes and cardiovascular disorders. Key Goals By proteomics determine which brain proteins in hippocampus and hypothalamus are up- or down-regulated in a BACE1-dependent manner following chronic high fat feeding. Validate the top proteomic hits by immunoblotting, mRNA and/or ELISA analysis in the appropriate brain areas. Attempt to correlate changes in key signalling pathways with the phenotypic and metabolic characteristics of BACE1 null (resistant to obesity and diabetes) and BACE1-knock-in (increased susceptibility to diabetes) mice.