TAU team discovers genetic link between autism and Alzheimer’s

Lack of a single gene — ADNP — could be the common cause of conditions that affect males and females differently

Prof. Illana Gozes (Courtesy)
Prof. Illana Gozes (Courtesy)

A Tel Aviv University team may have discovered the key to solving two seemingly different medical issues, which affect two very different populations.

A gene called ADNP could be responsible for causing higher levels of autism in boys — who suffer from the condition far more than girls do — as well as the increased levels of Alzheimer’s disease in elderly women.

According to Tel Aviv University’s Prof. Illana Gozes, “If we understand how ADNP, an activity-related neuroprotective protein, which is a major regulatory gene, acts differently in males and females, we can try to optimize drugs for potential future therapeutics to treat both autism and Alzheimer’s disease.”

Gozes holds the Lily and Avraham Gildor Chair for the Investigation of Growth Factors and is director of the Adams Super Center for Brain Studies at the Sackler Faculty of Medicine and a member of Tel Aviv University’s Sagol School of Neuroscience. For more than a decade, her team has been researching how ADNP, a major regulatory gene in humans, and its NAP derivative, affects a series of age- and gender-related conditions. Gozes is one of the world’s greatest experts in the area.

ADNP, or activity-dependent neuroprotective protein, is actually used as the name for the gene that encodes a protein called activity-dependent neuroprotector homeobox (the term “gene” and “protein” are generally applied interchangeably to ADNP in scientific literature). In studies over the past 15 years, scientists, including Gozes, have found that ADNP mutations can cause not only autism, but also Alzheimer’s.

In a study last year, for example, Gozes and the TAU team discovered how loss of NAP, a snippet of ADNP essential for brain formation, exposes cells to physical damage that eventually destroys them, triggering dementia-related diseases like Alzheimer’s. However, applying proteins with NAP-like properties to cells makes them healthy again — opening the door to possible treatments for Alzheimer’s and other degenerative diseases.

The current study, published this month in the Journal of Translational Psychiatry, sheds even more light on how ADNP affects Alzheimer’s patients — and provides insights into how the gene could affect males and females differently. In the study, Prof. Gozes and her team examined the behavioral response of male and female mice — both ADNP-altered and normal — to different cognitive challenges and social situations. To do so, they removed one copy of the ADNP gene from some mice, and then examined their respective responses to unfamiliar objects, odors, and other mice.

Their results revealed sex-specific learning and memory differences in the mice. In the younger male mice, the lack of ADNP caused deficiencies in object recognition and social memory, typical of autistic behavior. However, for older females, the removal of the gene caused them to withdraw and become more socially deficient, a hallmark of dementia-related diseases, especially Alzheimer’s. According to the study, “given the sex and genotype differences in ADNP positive or negative mice, we were interested to see if ADNP expression is sex-dependent in the hippocampus, a brain area directly associated with learning and memory.”

The results showed, for the first time, that there was a gender-related — and age-related — difference in the effect of ADNP on mouse behavior, said Gozes. The next step, of course, is to expand the study and extend it to human clinical trials. “This study emphasizes the need to analyze men and women separately in clinical trials to find cures for diseases, because they may respond differently,” she explained.

“ADNP may be new to the world of autism, but I have been studying it for 15 years,” added Prof. Gozes. “Its gender-dependent expression changes male and female chemical tendencies toward different neurological disorders. Male and female mice may look the same and their brains may look the same, but they are not. When the expression of ADNP is different, it may cause different behaviors and different cognitive abilities.”

Further work is needed, added the professor, but the team’s research could one day turn into a treatment to alleviate, or even reverse, Alzheimer’s disease, as well as autism.

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