Nonhuman Amyloid Oligomer Epitope Reduces Alzheimer’s-Like Neuropathology in 3xTg-AD Transgenic Mice

Abstract

Accumulation of beta-amyloid (Aβ) is an important pathological event in Alzheimer's disease (AD). It is now well known that vaccination against fibrillar Aβ prevents amyloid accumulation and preserves cognitive function in transgenic mouse models. To study the effect of vaccination against generic oligomer epitopes, Aβ oligomers, islet amyloid polypeptide oligomers, random peptide oligomer (3A), and Aβ fibrils were used to vaccinate 3xTg-AD, which develop a progressive accumulation of plaques and cognitive impairment. Subcutaneous administration of these antigens markedly reduced total plaque load (Aβ burden) and improved cognitive function in the 3xTg-AD mouse brains as compared to controls. We demonstrated that vaccination with this nonhuman amyloid oligomer generated high titers of specifically antibodies recognizing Aβ oligomers, which in turn inhibited accumulation of Aβ pathology in mice. In addition to amyloid plaques, another hallmark of AD is tau pathology. It was found that there was a significant decline in the level of hyper-phosphorylated tau following vaccination. We have previously shown that immunization with 3A peptide improves cognitive function and clears amyloid plaques in Tg2576 mice, which provides a novel strategy of AD therapy. Here, we have shown that vaccination with 3A peptide in 3xTg-AD mice not only clears amyloid plaques but also extensively clears abnormal tau in brain.