2024-01-28 23:55:38
Simply activating a certain brain protein may protect women from Alzheimer’s
Time: January 29, 2024
Source: Sci Adv
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A new study from Karolinska Institute suggests that activating a certain brain protein may protect women from neurodegenerative diseases such as Alzheimer’s disease.
“Cholesterol turnover and sex hormones are factors that can be modified. Our results suggest that they may become potential therapeutic targets for several neurodegenerative diseases in the future.” Karolinska Institutet Neurobiology, Nursing Science & Society said Silvia Maioli, associate professor in the department and lead researcher on the study.
The study in mice shows that activating the brain protein CYP46A1 protects women from neurodegenerative diseases such as Alzheimer’s disease.
This protein converts excess cholesterol in the brain into a cholesterol product called 24s-hydroxycholesterol (24SOH). The study, conducted in male and female mice, increased 24SOH production by increasing levels of the CYP46A1 protein. In females, the researchers were able to observe healthier neurons, better memory abilities and higher estrogen activity, both during menopause and during aging. These effects were not seen in male mice.
Measurements of 24SOH in the cerebrospinal fluid of Alzheimer’s patients showed that higher 24SOH levels were associated with lower levels of Alzheimer’s disease markers such as tau, but only in women.
Two-thirds of people with Alzheimer’s disease are women, and premature menopause is a specific risk factor for cognitive decline. Menopause is characterized by a decrease in estrogen, a hormone produced not only in the ovaries but also in the brain, where it is critical for maintaining the health and function of neurons. Research shows that activation of CYP46A1 increases estrogenic activity in the brains of menopausal and aged female mice, making CYP46A1 a potential female-specific therapeutic target.
Silvia Maioli said: “Previous studies have shown that low-dose anti-HIV drug Efavirenz can pharmacologically activate CYP46A1. We believe that targeting cholesterol metabolism with a CYP46A1 activator such as Efavirenz may provide a way to promote estrogen-mediated Alzheimer’s disease. Neuroprotection in women at risk for Alzheimer’s disease offers a new approach.”
The research included experiments on genetically modified mice, including behavioral studies and molecular analyses. Researchers explored the biological mechanisms of cultured hippocampal neurons. To demonstrate the clinical relevance of these findings, we collaborated with the groups of Miia Kivipelto and Bengt Winblad from the Memory Clinic of Karolinska University Hospital, Henrik Zetterberg and Kaj Blennow from Gothenburg, and Griffiths from Swansea University to examine a group of patients. Cerebrospinal fluid was measured for biomarkers and analyzed for sex segregation.
CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in ovariectomized mice.
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