The Role of Amyloid-β Oligomers in Toxicity, Propagation, and Immunotherapy

Abstract

The incidence of Alzheimer's disease (AD) is growing every day and finding an effective treatment is becoming more vital. Amyloid-β (Aβ) has been the focus of research for several decades. The recent shift in the Aβ cascade hypothesis from all Aβ to small soluble oligomeric intermediates is directing the search for therapeutics towards the toxic mediators of the disease. Targeting the most toxic oligomers may prove to be an effective treatment by preventing their spread. Specific targeting of oligomers has been shown to protect cognition in rodent models. Additionally, the heterogeneity of research on Aβ oligomers may seem contradictory until size and conformation are taken into account. In this review, we will discuss Aβ oligomers and their toxicity in relation to size and conformation as well as their influence on inflammation and the potential of Aβ oligomer immunotherapy.

Keywords: Amyloid-β; Immunotherapy; Inflammation; Oligomers; Size; Toxicity.

Fig. 1

The relationship between the size of Aβ assemblies and their toxic effects. Over produced native Aβ peptides undergo misfolding and form aggregates of different sizes and shapes. As the size of the assemblies increases, the potency of their toxic effects decreases maintaining an inverse correlation. For Aβ, toxic oligomers likely range from 8-24 mers while α-syn oligomers are 6-18 mers and tau oligomers are 3-15 mers. These n-mers cause neuronal toxicity either directly or by building up the higher aggregates. As these aggregates mature more into fibrils (bottom part of the funnel), they become less potent in their toxicity.

Fig. 2

The relationship between the Aβ assemblies and their toxicity based upon binding with fluorescent probes. As bis-ANS binding decreases, ThT binding increases indicating fibril formation and decreased toxicity (in percentage). ThT and bis-ANS binding to proteins are mostly used to confirm their fibrillar or oligomeric nature, respectively (more hydrophobic). Even though ThT reacts with the prefibrillar oligomers, its strongest association occurs only in the presence of mature fibrils. Amyloid oligomers show maximum toxicity, whereas, more homogeneous fibril species (~ 100% fibrils) show less toxicity. On the other hand, bis-ANS interacts most strongly (~ 100%) with the oligomers which show the highest toxicity. As the oligomers develop into larger and more stable aggregates, bis-ANS binding diminishes and so does the toxicity.

Fig. 3

Smaller aggregates are effective and potent seeds for the spreading of Aβ. Intact mature fibrils might induce larger aggregates which are localized to the induction site. Sonicated fibrils form smaller assemblies with larger numbers of nucleation sites that seed more potently in local regions and can travel between anatomically connected regions, thus inducing aggregates in distal regions.