Amyloid-beta Peptides are Generated in Mitochondria-Associated Endoplasmic Reticulum Membranes

Extracellular aggregates of amyloid-beta peptides (A beta) are a hallmark in Alzheimer's disease (AD) brains. Recent findings suggest that A beta is generated intracellularly and potential production sites include endosomes and trans-Golgi network. We determined the production of A beta in subcellular fractions isolated from mouse brain. We found that a considerable amount of A beta is produced at mitochondria-endoplasmic reticulum (ER) contact sites including outer mitochondrial membrane and mitochondria-associated ER membranes. Enhanced A beta production at this site may disturb ER, mitochondrial and mitochondria-ER contact site function. This may be one key step in the cascade of events eventually leading to neurodegeneration in AD.