P002 - THE ROLE OF CELL STRESS IN DRIVING PROTEIN AGGREGATION WITHIN CONTROL IPSC-DERIVED NEURONS (ID 1261)

Abstract

Aims

Increasing evidence suggests Alzheimer's disease (AD) pathogenesis is not limited to the neuronal compartment but strongly interacts with immunological mechanisms in the brain. There are many factors causing neuronal stress and producing a cytotoxic environment, such as endoplasmic reticulum stress and release of proinflammatory cytokines like Interleukin-1 beta (IL-1β) This can sequentially cause intracellular changes to highly sensitive neurons, leading to misfolding and aggregation of amyloid-beta (Aβ), tau and alpha-synuclein (αSyn) proteins and produce neurotoxic species that leads to neuroinflammation and neuronal death. This study uses normal neurons under different physiological stressors to evaluate how they disrupt protein homeostasis and lead to protein aggregation in a sporadic AD-like manner. To achieve this, aggregates formed within the cell and released in the secretome over time were assessed.

Methods

Control iPSC-derived neurons at early maturation stages were exposed to cell stressors such as thapsigargin, tunicamycin and human IL-1β for 20 days, to determine their influence on the number of Aβ and αSyn aggregates released by neurons as well as formed inside the cells. Cell culture media was collected every 5 days and lysates were collected every 10 days to observe aggregate changes and the level of cell death.

Results

Preliminary data have shown 100 ng/mL tunicamycin and 10 ng/mL IL-1β were able to induce an abnormal release of Aβ and αSyn aggregates in day 70 neurons.

Conclusions

Understanding what stresses cause the release of toxic oligomers will provide more insight into what can cause or contribute to sporadic AD and help find therapeutic treatments.

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