Alzheimer's disease (AD) is marked by progressive neurodegeneration and cognitive impairment, with a growing body of evidence indicating the critical role of mitophagy dysfunction in its pathology. This research project, led by doc. MUDr. Martin Vyhnálek, Ph.D., at Motol University Hospital and co-led by Mgr. Dáša Bohačiaková, Ph.D., at Masaryk University, seeks to delineate the molecular underpinnings of mitophagy impairment in AD and leverage these insights into clinical applications. Initially, the study will evaluate a set of biofluid biomarkers linked to autophagy-lysosomal degradation in serum samples from individuals at various stages of AD as well as cognitively unimpaired controls. Subsequently, the research will focus on the longitudinal assessment of these biomarkers to predict disease progression in early AD stages. Importantly, the project will also explore brain-derived extracellular vesicles to assess whether they offer a more precise reflection of mitophagy impairment within the brain. Along with isolation and evaluation of EVs, we will also analyze metabolic signatures related to mitophagy dysfunction, including NAD+ levels and other energy metabolism enzymes, through a collaboration with the Fang Lab at the University of Oslo. Finally, our project will also conduct mechanistic studies on iPSC-derived neurons from patients with familial and sporadic AD to understand alterations in mitophagy and its consequences on axonal transport and mitochondrial integrity. These experiments will be complemented by the use of cerebral organoids, which will be used to validate the findings from iPSC-derived neurons and assess biomarker secretion, thereby enhancing our comprehension of AD pathology and facilitating the development of potential diagnostic and therapeutic strategies. This integrative approach combines molecular biology, genetics, and bioinformatics, providing profound insights into the dysfunctional processes at the heart of AD and paving the way for targeted interventions.

Cíle udržitelného rozvoje

Masarykova univerzita se hlásí k cílům udržitelného rozvoje OSN, jejichž záměrem je do roku 2030 zlepšit podmínky a kvalitu života na naší planetě.