A new study by Tel Aviv University purports to reveal the link between a key gene and the differences between the sexes in the development of brain-related pathologies, such as autism and Alzheimer’s disease.
The research indicates that the reason autism is more common among boys, and Alzheimer’s more common among women, may be because the gene, known as ADNP, which is crucial to brain development, differs in its impact on the brains of each gender. The researchers stress that these differences will have to be taken into account when developing potential remedies for these and other problems.
The study, published this week in the journal Translational Psychiatry, was conducted by a group of researchers head by Prof. Illana Gozes, a professor of clinical biochemistry and director of the department of human molecular genetics and biochemistry at Tel Aviv University.
According to Gozes, this is an important clue en route to decoding the mechanisms that generate brain pathologies in general, and gender differences in particular. “We believe that our findings, and the research that will follow in their wake, are likely to pave the way for developing drugs that will help millions all over the world,” she said.
Gozes discovered the ADNP gene in her lab 15 years ago. “The gene is responsible for creating the protein, also called ADNP, that is crucial for brain development in the fetus. We later found that ADNP has significant expression in the hippocampus of the brain, in an area that is directly connected to memory and learning ability.” Subsequent studies, she said, found that this gene is responsible for controlling two other genes: the gene considered the primary risk factor for Alzheimer’s, and one that is directly connected to a certain type of autism.
“The ADNP gene is central to brain development,” she says. “It’s the gene that enables the neural tube to close during the formation of the brain in mammals, and without it, essentially there is no brain. It is a central control with very significant expression.”
As a result, Gozes says she was not surprised to discover that it is linked to neurological phenomena like autism and Alzheimer’s. “Logic would indicate that there is a connection, but we did not expect to find such large differences between males and females.” There are three autistic boys for every autistic girl, while Alzheimer’s is more prevalent among women than men. “The ADNP gene, by virtue of it being such a central gene, apparently plays a central role in the development of these diseases,” Gozes says. “Of course we must continue to study this, and we are doing so.”
Gozes and her team used mice models, and “from the start we found that in the hippocampus of healthy [male] mice there is a higher amount of the ADNP protein than in females. When we examined the brains of humans who had undergone autopsies, we reached similar findings.”
The researchers then examined the influence of the ADNP in the hippocampus on the two important genes it controls that are linked to autism and Alzheimer’s. The findings showed that a lack of ADNP leads to a higher expression of the Alzheimer’s gene in females, while in males it increases the expression of the gene linked to autism.
To better understand ADNP’s impact, the researchers also studied mouse behavior. Using mice that had been genetically engineered to have low levels of ADNP, they exposed the mice to cognitive assignments and social situations. The study showed that the lack of the protein indeed affected the performance and behavior of male and female mice differently. The male mice suffered more serious impairments, with their ability to learn, their memory and their social memory affected. They had a harder time identifying new objects and other mice. In contrast, the female mice showed only a mild impairment in their social memory compared to mice with normal ADNP. However, the fact that there was social memory impairment in both genders hints at the link between ADNP and autism.
This research, she says, is important for another reason. “Our study stresses the neurological difference between men and women, and the need to examine the responses of the two genders separately, especially in clinical trials of the effectiveness of new drugs,” notes Gozes. “Following these findings we are continuing to investigate the brain mechanisms that cause these differences. We believe that we’ve discovered an important key that is likely to lay the groundwork for the development of effective remedies in the future.”
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