Apolipoprotein A-I Directly Interacts with Amyloid Precursor Protein and Inhibits Aβ Aggregation and Toxicity

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Abstract
Amyloid precursor protein (APP) is the source of the neurotoxic amyloid β (Aβ) peptide associated with Alzheimer's disease. Apolipoprotein A-I (apoA-I), a constituent of high-density lipoprotein complexes, was identified by a yeast two-hybrid system as a strong and specific binding partner of full-length APP (APPfl). This association between apoA-I and APPfl was localized to the extracellular domain of APP (APPextra). Furthermore, the interaction between apoA-I and APPfl was confirmed by coprecipitation using recombinant epitope-tagged APPextra and purified apoA-I. Several functional domains have been identified in APPextra, and we focused on a possible interaction between apoA-1 and the pathologically important Aβ peptide, because APPextra contains the nontransmembrane domain of Aβ. The binding between apoA-I and Aβ was saturable (Kd = 6 nM), specific, and reversible. APPextra also competed with apoA-I for binding to Aβ. Direct evidence for this interaction was obtained by the formation of an SDS-resistant Aβ−apoA-I complex in polyacrylamide gels. Competitive experiments with apolipoprotein E (isoforms E2 and E4) showed that apoA-I had a higher binding affinity for Aβ. We also found that apoA-I inhibited the β-sheet formation of Aβ with a mean inhibitory concentration close to that of α2-macroglobulin. Finally, we demonstrated that apoA-I attenuated Aβ-induced cytotoxicity. These results suggest apoA-I binds to at least one extracellular domain of APP and has a functional role in controlling Aβ aggregation and toxicity.