Intracellular Aβ42 aggregation leads to cellular thermogenesis

Abstract

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 (FPTs) 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 favoured under intracellular-mimicking ionic conditions, which could potentially promote thermogenesis. The latter will, in turn, trigger further nucleation events that accelerate disease progression.

IF1 Protein Controls Aging Rate

“…Body temperature is increased (at statistical significance), by around 0.1°C, in people with Alzheimer’s disease (from a meta-analysis, summarizing six independent studies, with a total of 90 Alzheimer’s patients and 78 healthy controls [194]). Perhaps (at least in part) because of thermogenesis by Aβ aggregation [195]. Where, in vitro , greater temperature promotes greater Aβ production [196] and greater Aβ aggregation [195, 197–200].…”

“…Where, in vitro, greater temperature promotes greater Aβ production [196] and greater Aβ aggregation [195,[197][198][199][200]. Thence positive feedback is possible: Aβ aggregation generates heat, driving more Aβ aggregation, which generates more heat, in a runaway loop.…”