Creating amyloid-beta requires the convergence of a protein called amyloid precursor protein (APP) and an enzyme that cleaves APP into smaller toxic fragments (beta-secretase or BACE). Both APP and BACE are common in the brain, so why don’t we all get Alzheimer’s?
Cultured hippocampal neurons and tissue from human and mouse brains have now revealed that healthy brain cells largely segregate APP and BACE-1 into distinct compartments as soon as they are manufactured, ensuring the two proteins don’t have much contact with each other. However, in conditions promoting greater production of amyloid-beta protein (an increase in neuronal electrical activity), the convergence of APP and BACE also increases.
The findings not only add to our understanding of how Alzheimer’s gets started, but also suggests a possible therapeutic target: molecules that can physically keep APP and BACE-1 apart.
 Activity-Induced Convergence of APP and BACE-1 in Acidic Microdomains via an Endocytosis-Dependent Pathway. Neuron. 79(3), 447 - 460.(2013).