The role of oxysterols in neurodegeneration : implications for cognitive function, maternal effects, and sex-specific differences

Abstract

It is widely proven that an imbalance of cholesterol homeostasis within the brain is linked to several neurodegenerative diseases and in particular, Alzheimer's disease (AD). The brain, an organ highly enriched with cholesterol, maintains cholesterol balance between the central nervous system and the peripheral circulation through the oxidized cholesterol products known as oxysterols. Additionally, the cholesterol in the brain serves as a precursor for steroid hormone synthesis. This thesis aims to decipher the impact of oxysterols on cognitive function and neurodegeneration, taking sex-differences into account.

In Papers I, II, and III, the role of brain oxysterol 24-hydroxycholesterol (24OH) and peripheral oxysterol 27-hydroxycholesterol (27-OHC) in cognition and neurodegeneration is explored. Specifically, Paper I studies the sex-dependent neuroprotective aspect of 24OH in mice, while Paper II investigates the detrimental effect of 27-OHC in comparison to other oxysterols and, in Paper III, through lifespan.

In Paper I, we focus on elucidating the biological function of 24OH in the hippocampus, a critical brain region for memory function, and its signaling pathways related to steroid hormone production. 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. CYP46A1 overexpression only improved memory performance and synaptic functions in aged female mice, having opposite effects in males. In vitro, we found that 24OH influenced estrogen signaling and neurosteroidogenesis. Additionally, when endocrine aging was assessed, CYP46A1 overexpression was able to counteract cognitive deficits in ovariectomized females while having no effects in males. Paper I also examines how AD biomarkers are related to 24OH levels based on gender. Cerebrospinal fluid analysis in an AD clinical cohort with no comorbidities revealed a potential correlation between 24OH and AD biomarkers only in women.

The effects of altered cholesterol metabolites, particularly 27-OHC, were studied in Papers II and III. Accumulation of 27-OHC in different mouse models revealed some novel insights into its role in cognition in Paper II. In detail, deletion of Cyp7B1 did not induce memory deficits in mice compared to the observed memory impairment in the CYP27A1 overexpressing mice, suggesting different molecular mechanisms underlying their phenotypic differences. In Paper III, we aimed to understand the possible link between prenatal 27-OHC exposure and increased vulnerability to developing neurodegenerative disorders. We investigated short—and long-term effects on offspring health after exposure to high levels of 27-OHC during pregnancy, and a cognitive impact was found during aging.

The findings presented in this thesis shed light on novel roles of oxysterols, particularly 24OH and 27-OHC, concerning cognition, aging, and neurodegeneration. This study strengthens the notion that sex differences and early stages of life may be crucial factors in the pathogenesis of neurodegenerative diseases. This research proposes that modulating 24OH and 27-OHC levels could be a potential therapeutic and preventive target for neurodegeneration, particularly AD.