Regulated Proteolysis of RAGE and AβPP 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-β (Aβ) from the blood across the blood-brain-barrier into the brain. Oligomeric Aβ peptides disturb synaptic function in the brain and are believed to contribute to the development of AD. Aβ peptides are released from the amyloid-β protein precursor (AβPP) after sequential proteolysis by β- and γ-secretases but α-secretase-mediated cleavage of AβPP prevents Aβ generation. Insulin influences Aβ production by modulating α-secretase activity and Aβ 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 γ-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 Aβ peptide transport across the blood-brain-barrier. Current data suggest that the sequential proteolysis of RAGE is homologous to AβPP processing. [ABSTRACT FROM AUTHOR]