New thesis sheds light on the role of oxysterols in neurodegeneration
Hi María Latorre Leal, doctoral student at the Division of Neurogeriatrics. On April 26 you will defend your thesis "The role of oxysterols in neurodegeneration : implications for cognitive function, maternal effects, and sex-specific differences". What is the main focus of the thesis?
Disrupted cholesterol homeostasis in the brain impacts the pathogenesis of AD. The brain is one of the most cholesterol-enriched organs, where some oxidized cholesterol products called oxysterols maintain cholesterol balance, and steroid hormone synthesis takes place. This thesis aims to decipher the impact of oxysterols, specifically 24S-hydroxycholesterol (24OH) and 27-hydroxycholesterol (27-OHC) on cognitive function and neurodegeneration. For this purpose, we used different mouse models where cholesterol metabolism is altered and in vitro primary cultures of neurons. Additionally, the study on 24OH took a further translational approach using human CSF samples from a memory clinic cohort.
Which are the most important results?
The findings presented in this thesis shed light on novel roles of oxysterols, particularly 24OH and 27-OHC, concerning cognition, aging, and neurodegeneration.
Experiments on CYP46A1 overexpressing mice demonstrated that the CYP46A1 metabolic product, 24OH, impacts cognitive functions during chronological and endocrine aging in a sex-dependent manner. Additionally, CSF analysis in an AD clinical cohort with no comorbidities revealed a potential correlation between 24OH and AD biomarkers only in women. Accumulation of 27-OHC in different mouse models revealed some novel insights into its role in cognition. Furthermore, we found a possible link between prenatal 27-OHC exposure and increased vulnerability to developing neurodegenerative disorders.
Our results strengthens the notion that sex differences and early stages of life may be crucial factors in the pathogenesis of neurodegenerative diseases.
How can this new knowledge contribute to the improvement of people's health?
The conclusions drawn from this thesis indicate that future treatments for AD should be multifaceted, addressing multiple modifiable factors. Given the complexity of this disease, aspects such as cholesterol metabolism and sex should be included when designing therapeutic strategies. Additionally, this research proposes that modulating 24OH and 27-OHC levels could be a potential therapeutic and preventive target for neurodegeneration, particularly AD.
What's in the future for you? Will you continue to conduct research?
Yes, I would like to continue researching neurodegenerative disorders, in particular AD. I consider unraveling the mechanisms behind AD pathology to be one of the keys to finding a multitarget approach to AD treatments.