Alzheimer's, the activation of a brain protein can protect women

The activation of a particular brain protein (CYP46A1) could protect women from developing neurodegenerative diseases like the disease of Alzheimer's. the conclusion of a new study, published on Sciences Advances, driven by Silvia Maioliassociate professor at the Department of Neurobiology at the Karolinska Insitutet in Stockholm, who studied the protective effects of the protein first on mice and then on humans.

The role of estrogen on cognitive decline

Alzheimer's disease affects around 600 thousand people over 65 in Italy alone and 70% of cases are women. More and more studies identify menopause and the consequent drop in estrogen as a factor dementia risk factor, which becomes evident when one reaches an advanced age. In fact, with the end of the fertile age, women's brains also change, not only the functioning of their ovaries: during menopause the woman undergoes a fphysiological decrease in estrogenhormones produced not only by the ovaries, but also in the brain and essential for maintaining brain health and the learning ability from the memory. These hormones also perform a protective function against cell death andinflammation which favors the formation of Beta Amyloid plaques, the accumulation of which is one of the causes of Alzheimer's disease. Among other things, it has been seen that the early menopausebefore the age of 45 and the early menopausebefore the age of 40, accelerate cognitive deteriorationup to triple it (with higher levels of tau and amyloid protein tangles in the brain).

Why are men less affected by dementia? Among the hypotheses is the fact that only in humans is thearomastasisan enzymatic system responsible for conversion of androgen hormones (including testosterone) in estrogens: at an advanced age, compared to menopausal women, men could therefore have a greater number of estrogens in their brain (protective against Alzheimer's and dementia).

How to protect women from cognitive decline: what we know

Is there a way to prevent cases of dementia in women? We know that constant physical exercise (and it's never too late to abandon a sedentary lifestyle) and a healthy diet (particularly the MIND diet) are associated with a reduced risk of dementia in both men and women. Also there
hormone replacement therapy (HRT)
administered in the period in which the first symptoms of menopause begin, it seems associated with a reduced risk of Alzheimer's disease and dementia, even if the studies conducted so far are by no means conclusive on the topic. It is clear that HRT protects the brain by preventing hot flashes, sugar drops, disconnection of neurotransmitters, vasoconstriction and arterial hypertension, but for now we have no evidence that hormone replacement therapy also protects against Alzheimer's, however certainly improves cognitive function synthesizes Rossella Nappi, director of the Endocrinological Gynecology and Highly Complex Menopause Unit of the Irccs San Matteo Foundation of the University of Pavia. However, the Swedish researchers wanted to go further by studying brain enzymes and proteins with the goal of finding a way to protect women from developing Alzheimer's disease.

What does the CYP46A1 protein do

Scientists have been working on CYP46A1 protein ,which has an important function in the brain, i.e eliminate excess cholesterol
turning it into a product called 24S-hydroxycholesterol (24SOH). We have seen that when CYP46A1 levels increase in the brain of mice and subsequently increases the production of 24SOH, females have healthier neurons and a higher estrogenic activity in a brain region essential for memory, the hippocampus, explains Professor Silvia Maioli.

The study on mice: better memory and learning abilities

In line with this data, i female mice with levels

high in CYP46A1 show better learning and memory skills. Just as in humans, as mice age, their memory worsens compared to young mice, and the same is true for menopausal mice compared to non-menopausal mice. The Karolinska researchers observed that activation of CYP46A1 appears to be able to counteract memory loss during both aging and menopause, exclusively in female mice.

What happens to male mice

In male mice, however, activation of CYP46A1 causes worsening of memory and the accumulation of the male hormone di-hydro-testosterone in the brain, which blocks the protective effects of 24SOH, including the activation of estrogen receptors. .

The results therefore suggest that the production of 24SOH can compensate for the lack of estrogen, perhaps by better exploiting the hormone through more abundant receptors. They also suggest that upregulation of CYP46A1 might protect against cognitive decline seen after menopause.

Human studies

The results obtained in mice were subsequently validated by studies on men and women suffering from Alzheimer's disease or cognitive decline (about 90 people with an average age of 65 years, half of which were women) in which 24SOH was measured in the spinal fluid. Higher levels of 24SOH correspond to lower levels of Alzheimer's pathological markers such as tau protein, but only in women. It suggests that high levels of CYP46A1 and 24SOH may have a protective effect in Alzheimer's disease exclusively for females, underlines the researcher.

The drug Efavirenz against HIV is a possible new therapeutic approach

How do you activate the CYP46A1 protein? the drug, in reality, already exists. Previous research has shown that CYP46A1 can be activated by low doses of an HIV drug called
Efavirenz. This new study suggests that CYP46A1 activators such as Efavirenz may offer a new therapeutic approach to promote estrogen-mediated brain protection in women at risk of Alzheimer's disease, for example women with early menopause concludes Silvia Maioli. The possibilities of increasing estrogen activity in women's brains have the potential to become a new preventive therapy against terrible diseases such as Alzheimer's.

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