Apolipoprotein E co-localizes with newly formed amyloid β-protein (Aβ) deposits lacking immunoreactivity against N-terminal epitopes of Aβ in a genotype-dependent manner

Different types of amyloid beta-protein (A beta)-containing plaques occur in brains of Alzheimer's disease (AD) patients. Diffuse plaques seen during early stages of AD differ from neuritic plaques in later stages both with respect to the length of the A beta peptides and the presence of other proteins, e.g., apolipoprotein-E (apoE). Since apoE is involved in A beta transport and clearance, and the epsilon 4-allele of the apolipoprotein-E gene (APOE) is a major risk factor for sporadic AD, it is plausible to speculate that apoE plays a pathophysiological role in the initiation of A beta deposition. To address the issue of whether binding of apoE to A beta is involved in initial A beta deposition, we studied the human medial temporal lobe of 60 autopsy cases encompassing the full spectrum of AD-related pathology. In temporal lobe regions, which become involved for the first time at a given stage of beta-amyloidosis, all plaques represent newly formed plaques, and these were studied with immunohistochemical methods. ApoE was present in 36 cases, and was frequently co-localized with newly formed A beta deposits detectable with anti-A beta(42) but not with antibodies raised against N-terminal epitopes of A beta. In 10 additional cases, immunoreactivity against apoE was completely lacking in newly formed plaques, which, at the same time, displayed immunoreactivity against N-terminal epitopes of A beta. The failure of N-terminal epitopes of A beta to co-localize with apoE in newly formed plaques indicates that these deposits presumably contain apoE-A beta complexes, in which the N-terminal epitopes of A beta are often concealed after complexing with apoE, thus preventing subsequent binding of antibodies. Moreover, apoE-positive newly formed plaques were seen more frequently in APOE epsilon 4/4 cases than in non-APOE epsilon 4/4 individuals, thereby underlining the potentially crucial role of apoE for the development of A beta deposits.