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Trial Lecture – time and place
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Adjudication committee
- First opponent: Professor Manuel Zimmer, University of Vienna, Austria
- Second opponent: Professor Katja Kanninen, University of Eastern Finland,
- Third member and chair of the evaluation committee: Associate professor Hua Hu, University of Oslo
Chair of the Defence
Professor Magnar Bjørås, University of Oslo
Principal Supervisor
Associate Professor Evandro Fei Fang, Universitetet i Oslo
Summary
Dementia cases are projected to rise from 55 million in 2023 to 153 million by 2050, with Alzheimer’s disease (AD) accounting for 70%. While research has moved beyond amyloid-β (Aβ) plaques and tau tangles to include mitochondrial dysfunction, impaired autophagy, circadian disruption, and gut microbiota imbalance, effective AD therapies remain limited. My PhD work focuses on mitigating AD through enhancing mitochondrial quality and circadian regulation.
Nicotinamide adenine dinucleotide (NAD+), a key metabolite reduced in aging and AD, shows therapeutic potential by promoting mitochondrial autophagy (mitophagy). I demonstrated that NAD+ increases nuclear translocation of ATF5, which activates the mitochondrial unfolded protein response (UPRmt), enhances neuronal resilience, and reduces tau pathology in hTau.P301S mice. ATF5 also regulates mitophagy via PINK1/Parkin, revealing a coordinated NAD+-ATF5-UPRmt/mitophagy pathway (Paper 1).
Circadian disruption worsens AD. My work showed that NAD+ modulates the clock protein NR1D1 (Rev-erbα) in microglia, boosting Aβ clearance and improving cognition in AD models. This identifies NAD+-NR1D1 signaling as a novel mechanism linking circadian rhythm, microglial phagocytosis, and AD pathology (Paper 2).
Finally, I found that knockdown of NR1D1, a circadian rhythm factor, enhances autophagic flux and mitophagy, elevating SIRT1 and Cathepsin B levels, and restoring memory in both AD mouse and C. elegans models. These findings support NR1D1 reduction as a strategy to restore autophagy in AD (Paper 3).
Collectively, my research data show NAD+-dependent upregulation of UPRmt and circadian rhythm contributing to neuronal resilience; accordingly, fine-tuning the NAD+-UPRmt and the NAD+-circadian axes slow down AD progression. Further experiments in other AD rodent models as well as in AD iPSC-derived cellular and organoid systems are needed to validate our discoveries, before moving to any clinical settings.
Additional information
Contact the research support staff.