Haptoglobin: a new player in the crosstalk between Apolipoprotein E and Beta Amyloid

Objectives: Beta amyloid (beta-A) accumulation in brain is a driving force for Alzheimer's disease (AD) pathogenesis. Apolipoprotein E (ApoE) represents a critical player in beta-A homeostasis, but its role in AD progression is still controversial. We previously reported that Haptoglobin (Hpt), whose level increases during inflammation, binds ApoE and impairs apolipoprotein function in cholesterol homeostasis. Hpt was found associated with beta-A plaques, and shown to inhibit beta-A aggregation. The aim of this study was to evaluate whether the interaction between Hpt and ApoE affects the binding of ApoE to beta-A. Methods: ELISA, immunoprecipitation, and Western blotting, by using purified proteins or cerebrospinal fluid (CSF) were performed in this study. Results: We report here, for the first time, that Hpt forms SDS stable complexes with beta-A, and participates to the interaction between ApoE and beta-A, as shown by immunoprecipitating Hpt- betaA and Hpt- betaA -ApoE complexes from CSF. Furthermore Hpt acts as a positive effector by differently increasing the interaction of beta-A with ApoE2, ApoE3, or ApoE4 (ApoE2>ApoE3>ApoE4). Also, our results showed that the known Hpt activity in preventing oxidative modifications of ApoE is limited in the presence of beta Amyloid1-42. Conclusions: The interaction between Hpt and ApoE might represent a mechanism by which inflammation affects AD pathogenesis. We suggest that Hpt and ApoE functions in brain should be evaluated taking into account their interaction with beta-Amyloid.