APP and Alzheimer disease: High BACE1 expression is found in close proximity to Aβ plaques in human AD and APP transgenic mouse brains (Zhao et al., 2007; Devi and Ohno, 2013), while BACE1 and APP co-accumulated in peri-plaque dystrophic neurites function to generate Aβ, suggesting that local BACE1 elevation and de novo Aβ synthesis form a positive feedback loop to drive plaque growth (Zhang X-M.