Plaques made up of abnormal deposits of beta-amyloid protein are a hallmark of Alzheimer’s disease. The toxic buildup begins when the beta-secretase enzyme (BACE), working in concert with a partner enzyme, snips a small fragment of amyloid precursor protein (APP) and releases beta-amyloid from the cell membrane of neurons. The beta-amyloid can then gradually clump together to form the well-known plaques that may cause damage to brain cells. Now a new study primarily funded by NIA appearing in the April 10, 2012, issue of Nature Communications has revealed a previously unknown interaction between BACE and a large APP fragment called sAPPalpha that blocked the buildup of plaques in mice. The novel findings may lead to new therapeutic targets for Alzheimer’s researchers.
Scientists at the University of South Florida, Tampa, discovered that the sAPPalpha fragment, which is released from neurons at synapses (the tiny gap between neurons across which neurotransmitters travel during communication), interfered with BACE activities in mouse models with Alzheimer’s pathology. Increased levels of sAPPalpha blocked the ability of BACE to snip the APP protein and reduced levels of amyloid plaque buildup in the brains of the mice. Because lower than normal sAPPalpha levels are often found in people with Alzheimer’s, restoring or enhancing these levels may be one avenue to investigate for slowing onset or progression of the disorder.
Reference: Obregon D, et al. Soluble amyloid precursor protein-α modulates β-secretase activity and amyloid-β generation. Nature Communications. 2012 Apr 10;3:777. doi: 10.1038/ncomms1781.