Regulated Proteolysis of RAGE and A beta PP as Possible Link Between Type 2 Diabetes Mellitus and Alzheimer's Disease

Epidemiological studies have linked type 2 diabetes mellitus (T2DM) with an increased risk of developing Alzheimer's disease (AD). In T2DM, the elevated blood glucose level promotes formation of advanced glycation end products (AGEs). The receptor for AGEs (RAGE) is a type I membrane-protein and is also able to import amyloid-beta (A beta) from the blood across the blood-brain-barrier into the brain. Oligomeric A beta peptides disturb synaptic function in the brain and are believed to contribute to the development of AD. A beta peptides are released from the amyloid-beta protein precursor (A beta PP) after sequential proteolysis by beta- and gamma-secretases but alpha-secretase-mediated cleavage of A beta PP prevents A beta generation. Insulin influences A beta production by modulating alpha-secretase activity and A beta degradation. Recent publications demonstrate that RAGE is subjected to protein ectodomain shedding. Proteolysis of RAGE occurs constitutively and is inducible by activation of protein kinase C. Alpha-secretase-like enzymes release the ligand binding domain of RAGE from the cell surface and after that gamma-secretase processes the membrane-remaining part of RAGE. Proteolysis of RAGE may represent a regulatory mechanism in RAGE signal transduction and in addition may prevent A beta peptide transport across the blood-brain-barrier. Current data suggest that the sequential proteolysis of RAGE is homologous to A beta PP processing.