| Popis: |
In Alzheimer’s disease (AD), Amyloid-beta (Aβ) oligomers are considered an appealing therapeutic- and diagnostic target. However, to date, the molecular mechanisms associated with the pathological accumulation or structure of Aβ oligomers remains an enigma to the scientific community. Here we demonstrate the strong seeding properties of unique Aβ fragment signatures and show that the truncated Aβ peptides of residues Aβ1-23, Aβ1-24 and Aβ1-25, rapidly seed to form small, SDS-PAGE stable assemblies of ∼5kDa to ∼14kDa molecular mass range. Mass spectrometry analysis of SDS-PAGE fractionated and gel extracted oligomers revealed that the truncated Aβ isoforms of residues 1-23 to 1-25 form stable entities with low molecular weight (LMW) oligomers, which strongly resemble the regularly reported Aβ entities of putative dimeric or trimeric assemblies found in human post-mortem AD and Tg mouse brain extracts. Furthermore, electrophysiological recordings in the mouse hippocampus indicate that LMW Aβ assemblies formed by fragments Aβ1-23 to Aβ1-25 significantly impair long-term-potentiation (LTP) in the absence of full-length Aβ1-42. Extensive antibody screening highlights the important observation, that the LMW Aβ assemblies formed by these truncated Aβ peptides escape immuno-detection using conventional, conformation specific antibodies but, more importantly, the clinical antibody aducanumab. Our novel findings suggest that there are new Aβ target “loopholes” which can be exploited for the development of therapeutic antibodies with binding properties against stable target hotspots present in Aβ oligomers. We provide here a first example of a new class of monoclonal antibody with unique binding properties against LMW Aβ oligomers, in the absence of binding to large fibrillar Aβ assemblies, or dense amyloid plaques. Our research supports a novel, unparalleled approach for targeting early, pathological Aβ species during the insidious phase of AD and prior to the appearance of large oligomeric or protofibrilar assemblies. |
