Cellular and Molecular Signatures of the Aging Brain and Their Relationship with Alzheimer's Disease: A Special Focus on Mitochondria

Details

Supervisors

Kienlen-Campard, Pascal ; Suelves Caballol, Nuria

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences biomédicales, à finalité approfondie

Abstract

It has long been acknowledged that aging is a main risk factor for the development of many neurodegenerative diseases, particularly Alzheimer’s disease (AD). While the molecular mechanisms behind the shift between physiological and pathological aging remain largely unknown, cellular senescence has emerged as a key cellular process associated with aging. Triggered by a panoply of cellular stresses, senescence is characterized by a permanent arrest of cellular division and by an array of distinct phenotypic features that can exert toxic effects on surrounding tissues. Most importantly, senescent cells do not undergo apoptosis, resulting in their progressive accumulation in all tissues as we age. In the past years, evidence supporting a causative role of senescence in the onset of AD has emerged, but the specific underlying mechanisms through which senescence could trigger AD remain elusive. However, recent data suggest that senescence-induced mitochondrial dysfunction and impairment in mitophagy might be driving forces in AD pathogenesis. To test this theory, brain senescence, mitochondrial function, and mitophagy were characterized in the Terc-/- mouse model of senescence. Our results confirmed that telomere attrition and brain senescence progressively increased with each generation of Terc-/- mice and generally plateaued in G2 and G3-/- mice, making them the focus of our study. An HPLC analysis next indicated a clear perturbation in ATP, ADP, and AMP levels within G2Terc-/- brain tissue at 9 months, which was not observed in 5-month-old G3Terc-/- brain tissue, suggesting a potential age-related worsening of energy homeostasis in the model. Additional results obtained through an Electron Flow Assay demonstrated a significant decrease in mitochondrial electron transport chain (ETC) complex activity in both 9-month-old G2Terc-/- and 5-month-old G3Terc-/- brains, suggesting a defect in mitochondrial oxidative phosphorylation. However, we did not find any changes in the levels of key mitochondrial proteins and genes involved in the ETC complexes, suggesting that their overall structure remains preserved. Finally, two main mitophagy regulators were analyzed but no significant differences were observed in Terc-/- mice. Together, our results suggest a clear senescence-induced impairment in mitochondrial function, although the molecular drivers behind this impairment remain unknown.