科研之友
微信
新浪微博
Facebook
分享链接
摘要
In Alzheimer%26apos;s disease, substantial evidence indicates the causative role of soluble amyloid beta (A beta) aggregates. Although a variety of A beta assemblies have been described, the debate about their individual relevance is still ongoing. One critical issue hampering this debate is the use of different methods for the characterization of endogenous and synthetic peptide and their intrinsic limitations for distinguishing A beta aggregates. Here, we used different protocols for the establishment of prefibrillar A beta assemblies with varying morphologies and sizes and compared them in a head-to-head fashion. Aggregation was characterized via the monomeric peptide over time until spheroidal, protofibrillar, or fibrillar A beta aggregates were predominant. It could be shown that a change in the ionic environment induced a structural rearrangement, which consequently confounds the delineation of a measured neurotoxicity toward a distinct A beta assembly. Here, neuronal binding and hippocampal neurotransmission were found to be suitable to account for the synaptotoxicity to different A beta assemblies, based on the stability of the applied A beta aggregates in these settings. In contrast to monomeric or fibrillar A beta, different prefibrillar A beta aggregates targeted neurons and impaired hippocampal neurotransmission with nanomolar potency, albeit by different modalities. Spheroidal A beta aggregates inhibited NMDAR-dependent long-term potentiation, as opposed to protofibrillar A beta aggregates, which inhibited AMPAR-dominated basal neurotransmission. In addition, a provoked structural conversion of spheroidal to protofibrillar A beta assemblies resulted in a time-dependent suppression of basal neurotransmission, indicative of a mechanistic switch in synaptic impairment. Thus, we emphasize the importance of addressing the metastability of prefacto characterized A beta aggregates in assigning a biological effect.
- 出版日期2013-2-26
