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Different effects of CYP27A1 and CYP7B1 on cognitive function: Two mouse models in comparison.
Julen Goikolea1, Maria Latorre-Leal1, Christina Tsagkogianni1
1Karolinska Institutet, Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Stockholm, Sweden.
The Journal of Steroid Biochemistry and Molecular Biology
|August 30, 2023
Summary
High levels of oxysterol 27-hydroxycholesterol (27OHC) impact brain health. Cyp7B1 knockout mice show neuroprotection, unlike CYP27A1 overexpressing mice, suggesting differences in protective mechanisms against 27OHC toxicity.
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- Oxysterol 27-hydroxycholesterol (27OHC), produced by sterol 27-hydroxylase (Cyp27A1), impacts brain function.
- High 27OHC levels are linked to cognitive and synaptic dysfunction.
- Cytochrome P-450 oxysterol 7α-hydroxylase (Cyp7B1) catabolizes 27OHC.
Purpose of the Study:
- To compare neuroprotection in Cyp7B1 knockout and CYP27A1 overexpressing mouse models with high 27OHC levels.
- To investigate the roles of 7-HOCA and Cyp7B1 deletion in neuronal protection.
- To identify molecular mechanisms underlying differential responses to 27OHC accumulation.
Main Methods:
- Analysis of two mouse models: Cyp7B1 knock-out and CYP27A1 overexpressing.
- Assessment of learning, memory, neuronal morphology, and brain glucose uptake.
- RNA sequencing (RNA-seq) of neuronal nuclei.
- In vitro neuronal treatments with 27OHC and 7-HOCA.
Main Results:
- Cyp7B1 knock-out mice retained cognitive function and normal brain glucose uptake despite 27OHC accumulation.
- 7-HOCA treatment did not alter synaptic gene expression; 27OHC detrimental effects persisted in Cyp7B1 knockout neurons.
- RNA-seq revealed neuroprotective gene upregulation in Cyp7B1 knock-out mice and synaptic/metabolic gene downregulation in CYP27A1 overexpressing mice.
- Differences may stem from varying Cyp7B1 substrate levels (e.g., 25-hydroxycholesterol) between models.
Conclusions:
- Cyp7B1 deletion and its metabolite 7-HOCA do not appear to mediate the observed neuroprotection in Cyp7B1 knockout mice.
- CYP27A1 overexpressing mice may serve as a better model for studying 27-OHC-specific signaling.
- Understanding Cyp7B1 and Cyp27A1 pathways is crucial for neurodegenerative disease research, including Alzheimer's disease, and may reveal therapeutic targets.
