title: Globular and protofibrillar aβ aggregates impair neurotransmission by different mechanisms.
abstract: In Alzheimer's disease, substantial evidence indicates the causative role of soluble amyloid β (Aβ) aggregates. Although a variety of Aβ 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 Aβ aggregates. Here, we used different protocols for the establishment of prefibrillar Aβ 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 Aβ 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 Aβ assembly. Here, neuronal binding and hippocampal neurotransmission were found to be suitable to account for the synaptotoxicity to different Aβ assemblies, based on the stability of the applied Aβ aggregates in these settings. In contrast to monomeric or fibrillar Aβ, different prefibrillar Aβ aggregates targeted neurons and impaired hippocampal neurotransmission with nanomolar potency, albeit by different modalities. Spheroidal Aβ aggregates inhibited NMDAR-dependent long-term potentiation, as opposed to protofibrillar Aβ aggregates, which inhibited AMPAR-dominated basal neurotransmission. In addition, a provoked structural conversion of spheroidal to protofibrillar Aβ 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 Aβ aggregates in assigning a biological effect.
authors: Department of CNS Diseases Research Germany, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse, Biberach an der Riss D-88397, Germany. jensmoreth@gmail.com
authors: Jens
authors: J
authors: Moreth
authors: Katja S
authors: KS
authors: Kroker
authors: Daniel
authors: D
authors: Schwanzar
authors: Cathrin
authors: C
authors: Schnack
authors: Christine A F
authors: CA
authors: von Arnim
authors: Bastian
authors: B
authors: Hengerer
authors: Holger
authors: H
authors: Rosenbrock
authors: Lothar
authors: L
authors: Kussmaul
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission
chemical_list: D016229:Amyloid beta-Peptides