Endocytic pathways mediating oligomeric Abeta42 neurotoxicity.

One pathological hallmark of Alzheimer's disease (AD) is amyloid plaques, composed primarily of amyloid-beta peptide (Abeta). Over-production or diminished clearance of the 42 amino acid form of Abeta (Abeta42) in the brain leads to accumulation of soluble Abeta and plaque formation. Soluble oligomeric Abeta (oAbeta) has recently emerged to be as a likely proximal cause of AD. Here we demonstrate that endocytosis is critical in mediating oAbeta42-induced neurotoxicity and intraneuronal accumulation of Abeta. Inhibition of clathrin function either with a pharmacological inhibitor, knock-down of clathrin heavy chain expression, or expression of the dominant-negative mutant of clathrin-assembly protein AP180 did not block oAbeta42-induced neurotoxicity or intraneuronal accumulation of Abeta. However, inhibition of dynamin and RhoA by expression of dominant negative mutants reduced neurotoxicity and intraneuronal Abeta accumulation. Pharmacologic inhibition of the dynamin-mediated endocytic pathway by genistein also reduced neurotoxicity. These data suggest that dynamin-mediated and RhoA-regulated endocytosis are integral steps for oligomeric Abeta42-induced neurotoxicity and intraneuronal Abeta accumulation.