A Toxicogenic Interaction between Intracellular Amyloid-β and Apolipoprotein-E.
Arpan DeyAditi VermaUchit BhaskarBidyut SarkarMamata KallianpurVicky VishvakarmaAnand Kant DasKanchan GaraiOdity MukherjeeKunihiko IshiiTahei TaharaSudipta MaitiPublished in: ACS chemical neuroscience (2024)
Alzheimer's disease (AD) is associated with the aggregation of amyloid β (Aβ) and tau proteins. Why ApoE variants are significant genetic risk factors remains a major unsolved puzzle in understanding AD, although intracellular interactions with ApoE are suspected to play a role. Here, we show that specific changes in the fluorescence lifetime of fluorescently tagged small Aβ oligomers in rat brain cells correlate with the cellular ApoE content. An inhibitor of the Aβ-ApoE interaction suppresses these changes and concomitantly reduces Aβ toxicity in a dose-dependent manner. Single-molecule techniques show changes both in the conformation and in the stoichiometry of the oligomers. Neural stem cells derived from hiPSCs of Alzheimer's patients also exhibit these fluorescence lifetime changes. We infer that intracellular interaction with ApoE modifies the N-terminus of the Aβ oligomers, inducing changes in their stoichiometry, membrane affinity, and toxicity. These changes can be directly imaged in live cells and can potentially be used as a rapid and quantitative cellular assay for AD drug discovery.
Keyphrases
- cognitive decline
- single molecule
- high fat diet
- induced apoptosis
- mild cognitive impairment
- drug discovery
- cell cycle arrest
- risk factors
- oxidative stress
- neural stem cells
- end stage renal disease
- reactive oxygen species
- signaling pathway
- newly diagnosed
- ejection fraction
- atomic force microscopy
- living cells
- type diabetes
- cell death
- copy number
- adipose tissue
- high throughput
- insulin resistance
- high resolution
- molecular dynamics simulations
- single cell
- metabolic syndrome
- cerebrospinal fluid
- quantum dots
- patient reported