Quantitation of apoE domains in Alzheimer disease brain suggests a role for apoE in A beta aggregation

Apolipoprotein E (apoE) and apoE-derived proteolytic fragments are present in amyloid deposits in Alzheimer disease (AD) and cerebral amyloid angiopat hy (CAA). In this study, we examined which apoE fragments are most strongly associated with amyloid deposits and whether apoE receptor binding domains were present. We found that both apoE2- and apoE4-specific residues were p resent on plaques and blood vessels in AD and CAA. We quantified A beta pla que burden and apoE plaque burdens in 5 AD brains. ApoE N-terminal specific and C-terminal-specific antibodies covered 50% and 74% of A beta plaque bu rden, respectively (p < 0.003). Double-labeling demonstrated that the plaqu e cores contained the entire apoE protein, but that outer regions contained only a C-terminal fragment, suggesting a cleavage in the random coil regio n of apoE. Presence of N- and C-terminal apoE cleavage fragments in brain e xtracts was confirmed by immunoblotting. The numbers of plaques identified by the apoE N-terminal-specific antibodies and the apoE C-terminal-specific antibody were equal, but were only approximately 60% of the total A<beta> plaque number (p < 0.0001). Analysis of the size distribution of A<beta> an d apoE deposits demonstrated that most of the A beta -positive, apoE-negati ve deposits were the smallest deposits (less than 150 mum(2)). These data s uggest that C-terminal residues of apoE bind to A beta and that apoE may he lp aid in the progression of small A beta deposits to larger deposits. Furt hermore, the presence of the apoE receptor binding domain in the center of amyloid deposits could affect surrounding cells via chronic interactions wi th cell surface apoE receptors.