It is well accepted that dynamic oligomeric species formed from proteinaceous aggregates are implicated as the toxic agent for many human neurodegenerative diseases. The etiology of this group of disease is complex and compounded by several factors, including the specific structures and types of toxic oligomers and how they affect different brain regions. In this research, we replicate selective cell vulnerability, a phenomenon present in many neurodegenerative diseases including Alzheimer’s disease, using two model peptides and three brain regions: mouse suprachiasmatic nucleus (SCN), anterior hypothalamus (AH), and cerebral cortex. The first peptide model is a well-characterized amyloid model of toxic oligomers (KVKVLGDVIEV), termed KV11, known to form hexameric cylindrical oligomers. In parallel, we have also studied a mutation of KV11 (G6W). We show with ion mobility spectrometry-mass spectrometry (IMS-MS) that while the mutation of G6W potentially disrupted cylindrin formation, it facilitated G6W to form more structurally complex oligomers than KV11. X-ray crystallography showed that G6W forms a dodecamer made of hydrogen-bonded, twisted β-sheets in which pairs of β-sheets are mated through the interlinking of sidechains. Currently, the G6W dodecamer is not only the largest, but also the most structurally sophisticated model of toxic amyloid oligomers. We also showed that G6W toxicity was not due to membrane disruption, suggesting a more complex mechanism. However, the self-assembly and stability of oligomers can be affected by interactions with the cellular membrane mimetics (e.g., n-dodecyl-β-D-maltoside (DDM), a micelle-forming nonionic detergent). Finally, subtle chemical changes within the SCN+AH releasate were probed via liquid chromatography IMS-MS and several unique neuropeptides were identified and correlated to toxicity of KV11 or G6W. These peptides were previously linked to AD development and progression. Our study illuminates the feasibility using mouse brain tissues in replicating neurodegenerative conditions, and the powerful combination of IMS-MS and X-ray crystallography in structural elucidation of toxic amyloid oligomers.

An atomic view of unique amyloid dodecamer exhibits selective cell vulnerability among mouse brain tissues

ACS Fall 2021

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