A “significant overlap” exists between Alzheimer’s genes undergoing mutations and genes that impact autism and other intellectual disabilities, according to researchers at Tel Aviv University.
Scientists believe that autism results from mutations occurring randomly in the egg or sperm, or during pregnancy. One dominant gene whose mutations during pregnancy are known to lead to autism-related intellectual disabilities is activity dependent neuroprotective protein (ADNP).
The team at Tel Aviv University led by Prof. Illana Gozes of the Sackler Faculty of Medicine have now found that ADNP mutations continue to occur in old age and accumulate in the brains of Alzheimer’s disease patients.
The most common cause of dementia, Alzheimer’s disease affects approximately 5.8 million Americans alone, the vast majority age 65 and over. The number is expected to exceed over 14 million by 2050, according to the US Alzheimer’s Association.
“We discovered thousands of mutations in aging human brains, especially in the individual Alzheimer’s brains,” said Gozes, the first incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors. “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. Importantly, the cell skeleton/transport system includes the protein Tau, one of the major proteins affected in Alzheimer’s disease, which form the toxic neurofibrillary tangles.”
The ADNP protein was first discovered in Gozes’ laboratory in 1999. Postmortem examinations have subsequently indicated that it undergoes mutations in the aging brain of Alzheimer’s patients.
“Brain changes associated with Alzheimer’s disease may begin 20 or more years before any symptoms appear,” said Gozes. “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.”
Based on their findings published recently in the scientific journal Molecular Psychiatry, the researchers now propose what they describe as a “paradigm-shifting concept in the perception” of Alzheimer’s disease, in which uninherited genetic alterations passed on during cell division promote neurological disorders.
Through a technique called RNA-sequencing and further bioinformatics analysis, the team says they identified thousands of mutations occurring in the aging Alzheimer’s brain. Utilizing sophisticated cell cultures and live cell imaging technologies, they were able to identify protective molecules that could serve as potential drug candidates in the future.
“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, a key brain protein involved in Alzheimer’s disease and other brain diseases,” said Gozes. “We hope that new diagnostics and treatment modes will be developed based on our discoveries.”