Intracellular Aβ42 Aggregation Leads to Cellular Thermogenesis.
J Am Chem Soc
American Chemical Society (ACS)
MetadataShow full item record
Chung, C. W., Stephens, A. D., Konno, T., Ward, E., Avezov, E., Kaminski, C., Hassanali, A. A., & et al. (2022). Intracellular Aβ42 Aggregation Leads to Cellular Thermogenesis.. J Am Chem Soc, 144 (22), 10034-10041. https://doi.org/10.1021/jacs.2c03599
Funder: Cambridge Commonwealth, European and International Trust
Funder: Infinitus China Ltd.
The aggregation of Aβ42 is a hallmark of Alzheimer's disease. It is still not known what the biochemical changes are inside a cell which will eventually lead to Aβ42 aggregation. Thermogenesis has been associated with cellular stress, the latter of which may promote aggregation. We perform intracellular thermometry measurements using fluorescent polymeric thermometers to show that Aβ42 aggregation in live cells leads to an increase in cell-averaged temperatures. This rise in temperature is mitigated upon treatment with an aggregation inhibitor of Aβ42 and is independent of mitochondrial damage that can otherwise lead to thermogenesis. With this, we present a diagnostic assay which could be used to screen small-molecule inhibitors to amyloid proteins in physiologically relevant settings. To interpret our experimental observations and motivate the development of future models, we perform classical molecular dynamics of model Aβ peptides to examine the factors that hinder thermal dissipation. We observe that this is controlled by the presence of ions in its surrounding environment, the morphology of the amyloid peptides, and the extent of its hydrogen-bonding interactions with water. We show that aggregation and heat retention by Aβ peptides are favored under intracellular-mimicking ionic conditions, which could potentially promote thermogenesis. The latter will, in turn, trigger further nucleation events that accelerate disease progression.
Humans, Alzheimer Disease, Peptide Fragments, Thermogenesis, Amyloid beta-Peptides
Is supplemented by: https://doi.org/10.17863/CAM.82938
Medical Research Council (MR/K02292X/1)
Wellcome Trust (065807/Z/01/Z)
Wellcome Trust (203249/Z/16/Z)
External DOI: https://doi.org/10.1021/jacs.2c03599
This record's URL: https://www.repository.cam.ac.uk/handle/1810/338539
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/