Axonal generation of amyloid-β from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes

Axonal generation of Alzheimer's disease (AD)-associated amyloid-beta (A beta) plays a key role in AD neuropathology, but the cellular mechanisms involved in its release have remained elusive. We previously reported that palmitoylated APP (palAPP) partitions to lipid rafts where it serves as a preferred substrate for beta-secretase. Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are cholesterol-rich lipid rafts that are upregulated in AD. Here, we show that downregulating MAM assembly by either RNA silencing or pharmacological modulation of the MAM-resident sigma1 receptor (S1R) leads to attenuated beta-secretase cleavage of palAPP. Upregulation of MAMs promotes trafficking of palAPP to the cell surface, beta-secretase cleavage, and A beta generation. We develop a microfluidic device and use it to show that MAM levels alter A beta generation specifically in neuronal processes and axons, but not in cell bodies. These data suggest therapeutic strategies for reducing axonal release of A beta and attenuating beta-amyloid pathology in AD.