The Interplay Between Cholesterol and Amyloid- on HT22 Cell Viability, Morphology, and Receptor Tyrosine Kinase Signaling
JOURNAL OF ALZHEIMERS DISEASE(2023)
Abstract
Background: There is a lack of understanding in the molecular and cellular mechanisms of Alzheimer's disease that has hindered progress on therapeutic development. The focus has been on targeting toxic amyloid-beta (A beta) pathology, but these therapeutics have generally failed in clinical trials. A beta is an aggregation-prone protein that has been shown to disrupt cell membrane structure in molecular biophysics studies and interfere with membrane receptor signaling in cell and animal studies. Whether the lipid membrane or specific receptors are the primary target of attack has not been determined. Objective: This work elucidates some of the interplay between membrane cholesterol and A beta(42) on HT22 neuronal cell viability, morphology, and platelet-derived growth factor (PDGF) signaling pathways. Methods: The effects of cholesterol depletion by methyl-beta-cyclodextrin followed by treatment with A beta and/or PDGF-AA were assessed by MTT cell viability assays, western blot, optical and AFM microscopy. Results: Cell viability studies show that cholesterol depletion was mildly protective against A beta toxicity. Together cholesterol reduction and A beta(42) treatment compounded the disruption of the PDGF alpha receptor activation. Phase contrast optical microscopy and live cell atomic force microscopy imaging revealed that cytotoxic levels of A beta(42) caused morphological changes including cell membrane damage, cytoskeletal disruption, and impaired cell adhesion; cell damage was ameliorated by cellular cholesterol depletion. Conclusions: Cholesterol depletion impacted the effects of A beta(42) on HT22 cell viability, morphology, and receptor tyrosine kinase signaling.
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Key words
Alzheimer's disease,amyloid-beta,atomic force microscopy,cholesterol,HT22 cells,platelet-derived growth factor,receptor tyrosine kinase
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