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

Apolipoprotein E (apoE) and apoE-derived proteolytic fragments are present in amyloid deposits in Alzheimer disease (AD) and cerebral amyloid angiopathy (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 present on plaques and blood vessels in AD and CAA. We quantified A beta plaque 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 burden, respectively (p < 0.003). Double-labeling demonstrated that the plaque cores contained the entire apoE protein, but that outer regions contained only a C-terminal fragment, suggesting a cleavage in the random coil region of apoE. Presence of N- and C-terminal apoE cleavage fragments in brain extracts 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> and apoE deposits demonstrated that most of the A beta -positive, apoE-negative deposits were the smallest deposits (less than 150 mum(2)). These data suggest that C-terminal residues of apoE bind to A beta and that apoE may help aid in the progression of small A beta deposits to larger deposits. Furthermore, the presence of the apoE receptor binding domain in the center of amyloid deposits could affect surrounding cells via chronic interactions with cell surface apoE receptors.