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bioRxiv · 10.1101/2025.06.11.658821

Post-translational modifications distinguish amyloid-β isoform patterns extracted from vascular deposits and parenchymal plaques

Koutarapu, S.·Roberts, K. F.·Coyle, R. A.·Mehla, J.·Sato, C.·Zipfel, G. J.·Bateman, R. J.·Schwetye, K. E.·Mukherjee, S.
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Abstract

Deposition of amyloid-{beta} (A{beta}) aggregates is a core pathological hallmark of both cerebral amyloid angiopathy (CAA) and extracellular parenchymal plaques in Alzheimers disease (AD). While both disease processes share progressive, decades-long deposition of fibrillar A{beta} peptide, they differ in isoform composition. We hypothesized that post-translational modifications (PTMs) on A{beta} would also differ between CAA and parenchymal plaques. Using Lys-N enzymatic digestion followed by quantitative mass spectrometry, we profiled A{beta} isoforms and N-terminus PTMs (aspartic acid isomerization and pyroglutamate formation) across CAA severity and compared them to parenchymal plaque A{beta} in AD. Moderate to severe CAA primarily featured intact N-terminus (A{beta}1-x) ([~]95%) with minimal N-truncated species (A{beta}2-x, A{beta}3pGlu-x, A{beta}4-x), whereas parenchymal plaques displayed diverse N-terminus truncations and PTMs. Increasing CAA severity correlated with a shift from longer, hydrophobic C-terminal isoforms (A{beta}41, A{beta}42, A{beta}43) to shorter, less hydrophobic C-terminal isoforms (A{beta}37, A{beta}38, A{beta}39, A{beta}40). Importantly, moderate and severe CAA displayed minimal isomerization of Asp-1 and Asp-7 residues, which correlated significantly (r > 0.9) with shorter C-terminal isoforms (A{beta}37, A{beta}38, A{beta}39, A{beta}40). These patterns suggest distinct A{beta} aggregation mechanisms in CAA versus parenchymal plaques. We propose that the intact N-terminus found in CAA with limited Asp isomerization is due to its inclusion within the protofibril structure (less disordered and inaccessible to PTMs), unlike the parenchymal plaques, where the N-terminus is more disordered and accessible to PTMs. These biochemical differences may reflect distinct protofibril architectures with potential implications for biomarker development for early CAA detection and therapeutic targeting of vascular and parenchymal A{beta}.

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Koutarapu, S., Roberts, K. F., Coyle, R. A., Mehla, J., Sato, C., Zipfel, G. J., Bateman, R. J., Schwetye, K. E., Mukherjee, S.. 2025-06-15. Post-translational modifications distinguish amyloid-β isoform patterns extracted from vascular deposits and parenchymal plaques. https://doi.org/10.1101/2025.06.11.658821

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