Moderator of 1 Session
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FAMILIAL ALZHEIMER'S DISEASE NEUROPROGENITOR CELLS DISPLAY PRONOUNCED MITOCHONDRIAL METABOLISM ALTERATIONS
Abstract
Aims
The significant increase in life expectancy in the last 60 years urges the handling of age-associated diseases. Alzheimer's disease (AD) is currently considered the major cause of dementia. However, despite being one of the most studied neurodegenerative diseases, little therapeutic progress was achieved in the last decades. Familial Alzheimer’s disease comprises of 5% of the cases and display an early onset, making it a valuable model for the study of the disease. One of the hallmarks of AD is its mitochondrial metabolism disruption. Here, we aim to investigate the metabolic mechanisms which are altered in AD.
Methods
We successfully generated and characterized neuroprogenitor cells (NPCs) from familial AD, their respective isogenic controls, and healthy subjects-derived iPSCs. Our differentiation protocol makes use of a 15 days 3D embryoid body formation step, followed by FACS sorting of the NPC population (CD271-, CD44-, CD184+, CD24+, CD15-/+) which renders a population of more than 90% NPC. The overall expression of metabolic pathways proteins was determined by proteomics. Metabolic activity was assessed by measurements of mitochondrial respiration, glycolytic rate, and metabolic substrate usage.
Results
We report an overall decrease in glycolytic proteins expression and substrate usage, OCR and ECAR parameters.
Conclusions
Our results indicate that metabolic alterations are already perceivable in AD-derived NPCs, which can be a target for early intervention. References: 1. N. Gunhanlar et al., Mol Psychiatry 23, 1336-1344 (2018); 2. M. Oksanen et al., Stem Cell Reports 9, 1885-1897 (2017); 3. M. Trombetta-Lima et al., Cell Calcium 94:102362 (2021).