Endocytic pathways mediating oligomeric Aβ42 neurotoxicity

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