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

摘要

Different types of amyloid β-protein (Aβ)-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 Aβ peptides and the presence of other proteins, e.g., apolipoprotein-E (apoE). Since apoE is involved in Aβ transport and clearance, and the ε4-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 Aβ deposition. To address the issue of whether binding of apoE to Aβ is involved in initial Aβ 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 β-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 Aβ deposits detectable with anti-Aβ42 but not with antibodies raised against N-terminal epitopes of Aβ. 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 Aβ. The failure of N-terminal epitopes of Aβ to co-localize with apoE in newly formed plaques indicates that these deposits presumably contain apoE-Aβ complexes, in which the N-terminal epitopes of Aβ 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 ε4/4 cases than in non-APOE ε4/4 individuals, thereby underlining the potentially crucial role of apoE for the development of Aβ deposits.