Apolipoprotein E (apoE) is the only serum apolipoprotein that is also found in the extravascular fluid of the brain, where it is thought to play an important role in lipid transport in the central nervous system. In addition apoE has also been implicated in neural regenerative processes and in the etiology of Alzheimer's disease. Peptides derived from the receptor binding domain of apoE are biologically active and bind to low density lipoprotein (LDL) receptors and LDL receptor related protein. There is, however, no direct evidence that these apoE peptides are able to directly activate the endocytic process, either in the brain or elsewhere. In the present paper, we have used electron microscopy and video imaging fluorescence microscopy to investigate the effects of a peptide derived from the receptor binding domain of human apoE on endocytosis in cultured rat cortical neurons. We have found that this tandem dimer repeat peptide induces neuronal endocytosis via a receptor associated protein sensitive pathway. Although the peptide induces a rise in cytoplasmic calcium, this is not required for the induction of endocytosis. On the other hand, normal processing of the endocytic vesicles does appear to require the elevation of cytoplasmic calcium, since inhibition of the calcium response results in the accumulation of large endocytic vesicles.