Autosomal recessive hypercholesterolemia protein interacts with and regulates the cell surface level of Alzheimer's amyloid β precursor protein

The familial Alzheimer's disease gene product amyloid beta protein precursor (AbetaPP) is sequentially processed by beta- and gamma-secretases to generate the Abeta peptide. Although much is known about the biochemical pathway leading to Abeta formation, because extracellular aggregates of Abeta peptides are considered the cause of Alzheimer's disease, the biological role of AbetaPP processing is only recently being investigated. Cleavage of AbetaPP by gamma-secretase releases, together with Abeta, a COOH-terminal AbetaPP intracellular domain, termed AID. Hoping to gain clues about proteins that regulates AbetaPP processing and function, we used the yeast two-hybrid system to identify proteins that interact with the AID region of AbetaPP. One of the interactors isolated is the autosomal recessive hypercholesterolemia (ARH) adapter protein. This molecular interaction is confirmed in vitro and in vivo by fluorescence resonance energy transfer and in cell lysates. Moreover, we show that reduction of ARH expression by RNA interference results in increased levels of cell membrane AbetaPP. These data assert a physiological role for ARH in AbetaPP internalization, transport, and/or processing.