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

Accumulation of amyloid-beta (A beta) in plaques in the brain and in artery walls as cerebral amyloid angiopathy indicates a failure of elimination of A beta from the brain with age and Alzheimer's disease. A major pathway for elimination of A beta 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. The motive force for the elimination of A beta along this perivascular pathway appears to be the contrary (reflection) wave that follows the arterial pulse wave. Following injection into brain parenchyma, A beta rapidly drains out of the brain along basement membranes in the walls of cerebral arteries; such drainage is impaired in apolipoprotein E epsilon 4 (ApoE4) mice. For drainage of A beta to occur in a direction contrary to the pulse wave, some form of attachment to basement membrane would be required to prevent reflux of A beta back into the brain during the passage of the subsequent pulse wave. In this study, we show first that apolipoprotein E co-localizes with A beta in basement membrane drainage pathways in the walls of arteries. Secondly, we show by Atomic Force Microscopy that attachment of ApoE4/A beta complexes to basement membrane laminin is significantly weaker than ApoE3/A beta complexes. These results suggest that perivascular elimination of ApoE4/A beta 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/A beta/laminin interactions may increase the efficiency of elimination of A beta in the prevention of Alzheimer's disease. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. (c) 2015 Elsevier B.V. All rights reserved.