Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 144, Issue 22, Pages 10034-10041Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.2c03599
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Funding
- Alzheimer's Research UK (ARUK)
- Cambridge Trust
- Wolfson College
- Wellcome Trust [065807/Z/01/Z, 203249/ Z/16/Z]
- UK Medical Research Council (MRC) [MR/ K02292X/ 1]
- ARUK [ARUK-PG013-14]
- Michael J Fox Foundation [16238]
- Infinitus China Ltd.
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This study demonstrates that aggregation of A beta 42 in live cells leads to an increase in cell-averaged temperatures, which can be mitigated by treatment with an aggregation inhibitor. It also suggests that under intracellular-mimicking ionic conditions, aggregation and heat retention by A beta peptides are favored, potentially promoting thermogenesis.
Y The aggregation of A beta 42 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 A beta 42 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 A beta 42 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 A beta 42 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 A beta 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 A beta 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.
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