Understanding the mechanisms of Alzheimer's disease
Amyloid beta (Abeta) is a peptide believed to be the main element of amyloid plaques. These are deposits found in the brains of Alzheimer's disease (AD) patients. The amyloid precursor protein (APP) is a membrane protein expressed in various tissues and concentrated in the synapses of neurons. Cleavage (division) of the APP at certain sites (beta- and gamma-secretase cleavage sites) and ensuing formation of Abeta peptides play an important role in AD pathology. APP can also be cleaved by ±-secretase. The disintegrin and metalloproteinase ADAM10, a cell surface protein, appears to a major player in these processes, considering its adhesion and protease potential as well as cleavage function. Most treatment strategies for Alzheimer's disease focus on decreasing Abeta by lowering beta- and gamma-secretase activity. An alternative approach could be to increase alpha-secretase activity; however, the exact nature of alpha-secretase is still largely unknown. The 'Study and Identification of ADAM10 as neuronal a-secretase in relation to Alzheimer's disease' (Adamneuron) project is working to determine the role that ADAM10 plays in neuronal ±-secretase activity. Specifically, the EU-funded project is investigating whether it is involved in neuronal survival, if growth and neuroprotective factors can trigger its expression or activity, and if it is involved in memory and learning. To investigate ADAM10 functions in the brain, researchers generated ADAM10 conditional knockout (cKO) mice and limited ADAM10 inactivation in various cells. Alpha-secretase mediated processing of APP showed a marked decrease in neurons derived from embryonic cKO mice. These results reveal that ADAM10 is in fact the most important APP alpha-secretase in the brain. In other achievements to date, Adamneuron team members have developed and validated a neuroblastoma screening system. This will allow for screening of factors that influence alpha-secretase regulation, and provide knowledge on its mechanisms. As work continues, project partners will study ADAM10 in the mature brain, and thus Alzheimer's-like pathology. Project experiments will enhance understanding of ±-secretase in the brain and aim to contribute to the future development of novel AD therapies.
