Nonhuman Amyloid Oligomer Epitope Reduces Alzheimer’ s-Like Neuropathology in 3xTg-AD Transgenic Mice Suhail Rasool & Hilda Martinez-Coria & Saskia Milton & Charles G. Glabe Received: 15 March 2013 / Accepted: 30 May 2013 / Published online: 15 June 2013 # Springer Science+Business Media New York 2013 Abstract Accumulation of beta-amyloid (Aβ) is an impor- tant pathological event in Alzheimer’ s disease (AD). It is now well known that vaccination against fibrillar Aβ pre- vents amyloid accumulation and preserves cognitive function in transgenic mouse models. To study the effect of vaccination against generic oligomer epitopes, Aβ oligomers, islet amy- loid polypeptide oligomers, random peptide oligomer (3A), and Aβ fibrils were used to vaccinate 3xTg-AD, which de- velop a progressive accumulation of plaques and cognitive impairment. Subcutaneous administration of these antigens markedly reduced total plaque load (Aβ burden) and im- proved 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 vacci- nation. 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. Keywords Alzheimer’ s disease . 3A peptide . Amyloid beta . Tau pathology Introduction Alzheimer’ s disease (AD) is an irreversible, neurodegenera- tive disorder exhibiting an insidious onset and a gradual progressive course. AD is associated with progressive cog- nitive decline, neuronal loss, and the accumulation of senile plaques and neurofibrillary tangles in affected regions of the brain [1]. The original amyloid cascade hypothesis [2, 3] proposed that the accumulation of amyloid plaques was the principal factor in AD pathogenesis. Recent studies suggest that small soluble Aβ aggregates or oligomers may represent the primary pathogenic entities [4]. It is well established that individuals with AD show multifaceted cognitive impair- ments that progressively interfere with their day-to-day func- tioning and are characteristically distinct from those changes observed in normal aging [5]. At the neuropathological level, AD brains are marked by extracellular amyloid plaques, mainly composed of aggregated amyloid-β (Aβ) peptide, and by intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated tau protein [6, 7]. Aβ peptide is derived by sequential proteolytic cleavage of amyloid precur- sor protein (APP) by β-secretase and presenilin-dependent γ-secretase to yield Aβ42 and Aβ40 [8]. Mutations in the genes of APP [9] and presenilin-1 and presenilin-2 (PS-1 and PS-2) [10, 11] account for most familial early-onset cases of AD by enhancing Aβ production. Although mul- tiple other complex systems are likely involved in the pathogenesis of AD, there is substantial evidence that Aβ S. Rasool : S. Milton : C. G. Glabe Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA H. Martinez-Coria Department of Neurology and Institute for Memory Impairment and Neurological Disorders, University of California, Irvine, CA 92697, USA Present Address: S. Rasool (*) Department of Physiology and Neurosciences, New York University School of Medicine, New York, NY 10016, USA e-mail: suhailrasool@hotmail.com Mol Neurobiol (2013) 48:931–940 DOI 10.1007/s12035-013-8478-7