Endocytic pathways mediating oligomeric A[beta]42 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, knock-down 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.