Quantification of molecular interactions between ApoE, amyloid-beta (Aβ) and laminin: Relevance to accumulation of Aβ in Alzheimer’s disease

Accumulation of amyloid-β (Aβ) in plaques in the brain and in artery walls as cerebral amyloid angiopathy indicates a failure of elimination of Aβ from the brain with age and Alzheimer’s disease. A major pathway for elimination of Aβ and other soluble metabolites from the brain is along basement membranes within the walls of cerebral arteries that represent the lymphatic drainage pathways for the brain. Since Aβ40 is the predominant type of Aβ found in cerebral amyloid angiopathy, in the present study we tested the hypothesis that interactions of Aβ40 with protein components of cerebral vascular basement membranes, such as laminin, are stronger in the presence of ApoE3 than in the presence of ApoE4. Proteins (LN-511, ApoE3, or ApoE4) were immobilized on AFM probes using the amine–amine-reactive linker aldehyde–PEG–NHS. Force-spectroscopy experiments were performed to study the reciprocal influence of different isoforms of ApoE and Aβ on their binding interactions with laminin-511. The results show that apolipoprotein E co-localizes with Aβ in basement membrane drainage pathways in the walls of arteries. Moreover, all AFM measurements demonstrate that Aβ + ApoE3 complex has a stronger binding to laminin-511 than Aβ + ApoE4. These results suggest that perivascular elimination of ApoE4/Aβ complexes would be less efficient than with other isoforms of apolipoprotein E, thus endowing a higher risk for Alzheimer’s disease. Therapeutic correction for ApoE4/Aβ/laminin interactions may increase the efficiency of the elimination of Aβ in the prevention of Alzheimer’s disease.