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 β protein precursor (AβPP) is sequentially processed by β- and γ-secretases to generate the Aβ peptide. Although much is known about the biochemical pathway leading to Aβ formation, because extracellular aggregates of Aβ peptides are considered the cause of Alzheimer's disease, the biological role of AβPP processing is only recently being investigated. Cleavage of AβPP by γ-secretase releases, together with Aβ, a COOH-terminal AβPP intracellular domain, termed AID. Hoping to gain clues about proteins that regulates AβPP processing and function, we used the yeast two-hybrid system to identify proteins that interact with the AID region of AβPP. 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 AβPP. These data assert a physiological role for ARH in AβPP internalization, transport, and/or processing.