Linking Aβ and tau in the amyloid cascade through the intersection of their proteostasis networks

Lim, C. M.; Hardy, J.; Vendruscolo, M.

doi:10.1101/2025.03.28.646065

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bioRxiv · 10.1101/2025.03.28.646065

Linking Aβ and tau in the amyloid cascade through the intersection of their proteostasis networks

Lim, C. M.·Hardy, J.·Vendruscolo, M.

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Abstract

Amyloid plaques and neurofibrillary tangles are molecular hallmarks of Alzheimers disease. According to the amyloid cascade hypothesis, aberrant A{beta} and tau behaviours contribute synergistically to accelerate the Alzheimers pathology. However, the complex molecular mechanisms linking A{beta} and tau dysregulation remain to be fully characterised. To address this problem, we investigated the connection between A{beta} and tau through the protein homeostasis (proteostasis) network. We asked whether A{beta} proteostasis is linked to tau proteostasis. To answer to this question, we first mapped the proteostasis networks of A{beta} and tau, and then studied the interplay of these two networks, identifying the molecular chaperone HSP90 as a central hub. To test this hub role of HSP90, we observed in a cell model that HSP90 and its co-chaperone SUGT1 mediate tau phosphorylation via GSK-3{beta} in an A{beta}42-dependent manner. Furthermore, we also observed that in turn HSP90 and SUGT1 increase the intracellular concentration of A{beta}42. These results suggest that the HSP90/SUGT1 system may act as a hub in the amyloid cascade by lying at the intersection of the A{beta} and tau proteostasis networks.

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Lim, C. M., Hardy, J., Vendruscolo, M.. 2025-04-03. Linking Aβ and tau in the amyloid cascade through the intersection of their proteostasis networks. https://doi.org/10.1101/2025.03.28.646065

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