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Autism-Related Gene Mutations Occur in Alzheimer Patients

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Researchers believe that autism is caused by mutations in the egg or sperm or during pregnancy, particularly in the activity-dependent neuroprotective protein (ADNP) gene.

A new Tel Aviv University study published in Molecular Psychiatry found that ADNP mutations continue to occur in old age and accumulate in the brains of Alzheimer’s disease patients.

“We discovered thousands of mutations in aging human brains, especially in the individual Alzheimer’s brains,” explained lead author Prof. Ilana Gozes. It was in her lab that ADNP was first discovered 20 years ago.

“Brain changes associated with Alzheimer’s disease may begin 20 or more years before any symptoms appear,” she said.

“As neuronal damage increases, the brain can no longer compensate for the changes, and individuals show cognitive decline. Currently, the diagnosis of Alzheimer’s occurs when the brain damage of individual patients is already widespread so that current drugs can at most offer symptomatic relief. But they provide no cure.”

Caption to right: Prof. Illana Gozes of Tel Aviv University. Photo: courtesy

In their new study, Gozes and her Ph.D. students Yanina Ivashko-Pachima and Adva Hadar, in collaboration with Iris Grigg, Oxana Kapitansky and Gidon Karmon, propose a paradigm-shifting concept in the understanding of Alzheimer’s disease.

According to the research, uninherited genetic alterations passed on during cell division promote brain pathology. If so, this could provide an avenue for developing new diagnostic measures and therapies.

Potential drug candidates

Through a complete sequencing of protein-encoding DNA (a technique called RNA-sequencing) and further bioinformatics analysis, the team identified thousands of mutations in the aging Alzheimer’s brain.

“We were surprised to find a significant overlap in Alzheimer’s genes undergoing mutations with genes that impact autism, intellectual disability, and mechanisms associated with the cell skeleton/transport system health,” Gozes said.

“Importantly, the cell skeleton/transport system includes the protein Tau, one of the major proteins affected in Alzheimer’s disease and other brain diseases, which form the toxic neurofibrillary tangles.”

Further sophisticated cell cultures and live-cell imaging technologies enabled identification of protective molecules that could serve as potential drug candidates.

“We found in cell cultures that the ADNP-derived snippet, the drug candidate NAP, inhibited mutated-ADNP toxicity and enhanced the healthy function of Tau,” said Gozes.

In addition to her academic duties, Gozes is the chief scientific officer of Coronis Neurosciences, a company developing NAP for the treatment of ADNP syndrome, the autism spectrum disorder. The use of ADNP and related mutations for Alzheimer’s diagnosis and for ADNP-related peptide/peptide mimetics AD/ASD treatment is under patent protection.

“We hope that new diagnostics and treatment modes will be developed based on our discoveries,” she said of the new research into Alzheimer’s.

Gozes heads the Elton Laboratory for Molecular Neuroendocrinology at TAU’s Department of Human and Molecular Genetics, Sackler Faculty of Medicine. She is also a member of TAU’s Adams Super Center for Brain Studies and the Sagol School of Neuroscience.

Ph.D. student, Hadar’s work was co-supervised by co-author Prof. David Gurwitz of TAU’s Sackler Faculty of Medicine. Collaborating labs in the study included those of Vlasta Korenková (BIOCEV, Czech Republic), Michael Gershovits (Weizmann Institute of Science, Israel), C. Laura Sayas (Universidad de La Laguna, Tenerife, Spain), R. Frank Kooy (University of Antwerp, Belgium) and Johannes Attems (Newcastle University, UK).

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Schedule30 Sep 2023