Abstract
Alzheimer’s disease (AD) is a progressive disorder of the brain that gradually decreases thinking, memory, and language abilities. The aggregation process of amyloid β (Aβ) is a key step in the expression of its neurocytotoxicity and development of AD because Aβ aggregation and accumulation around neuronal cells induces cell death. However, the molecular mechanism underlying the neurocytotoxicity and cell death by Aβ aggregation has not been clearly elucidated. In this study, we successfully visualized real-time process of Aβ42 aggregation around living cells by applying our established QD imaging method. 3D observations using confocal laser microscopy revealed that Aβ42 preferentially started to aggregate at the region where membrane protrusions frequently formed. Furthermore, we found that inhibition of actin polymerization using cytochalasin D reduced aggregation of Aβ42 on the cell surface. These results indicate that actin polymerization-dependent cell motility is responsible for the promotion of Aβ42 aggregation at the cell periphery. 3D observation also revealed that the aggregates around the cell remained in that location even if cell death occurred, implying that amyloid plaques found in the AD brain grew from the debris of dead cells that accumulated Aβ42 aggregates.
Highlights
Alzheimer’s disease (AD) is a progressive disorder of the brain that gradually decreases thinking, memory, and language abilities
Rat adrenal pheochromocytoma PC12 cells, which were differentiated by 4.5 ng/ml nerve growth factor (NGF), were incubated with 20 μM Aβ42 and 30 nM QDAβ for 24 h
The combinations of quantum dot (QD) or QDAβ and Aβ42 exhibited almost the same result as Aβ42 alone. These results indicate that the addition of QDAβ had little effect on the viability of Aβ42-treated cells. 3D real-time imaging revealed that early aggregation at the cell periphery occurred after 8 h of incubation (Fig. 2A,B and Supplementary Movies S1 and S2)
Summary
Alzheimer’s disease (AD) is a progressive disorder of the brain that gradually decreases thinking, memory, and language abilities. Aβ affected the architecture of actin and the tubulin network in AD pathology[26] It is obscure whether changes in cell morphology derived from cell motility influence the polymerization and fibrillization of Aβ that exists in culture medium or on the cell membrane. It is unknown whether morphological changes of the cellular membrane, which occur after the formation of actin-dependent protrusions, affect Aβ aggregation in the environment close to the cell surface. 3D real-time observations using confocal laser microscopy revealed that Aβ42 preferentially started to aggregate on the dynamic cell surface where membrane protrusions frequently formed
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