Study shows how peptide inhibitor helps to treat Alzheimer’s and Huntington’s disease

According to the Alzheimer’s Association, around 11% of the population, comprising 65-year old and above—in the United States has been diagnosed with Alzheimer’s disease (AD), the most prevalent form of dementia that causes memory loss and cognitive impairment.

Study shows how peptide inhibitor helps to treat Alzheimer’s and Huntington’s disease
Xin Qi. Image Credit: Case Western Reserve University.

According to the World Health Organization, the number of individuals living with Alzheimer’s disease is expected to increase by millions each year.

Despite decades of research, scientists are still baffled as to what causes the brain disorder. And, there is no recognized treatment for it.

However, a new study published recently in Nature Communications by a group of researchers from Case Western Reserve University School of Medicine reveals that a crucial protein molecule plays a critical role in the accumulation of brain cholesterol, which causes Alzheimer’s disease.

Earlier this year, Xin Qi’s group at the School of Medicine discovered and copyrighted a peptide inhibitor in the hopes of curing Alzheimer’s disease and Huntington’s disease. According to Qi, mice treated with the peptide inhibitor showed 50% regained memory function in tests such as maze navigation.

The impact of Alzheimer’s disease

Alzheimer’s disease (AD) is an age-related neurodegenerative disease that causes progressive cell death, memory loss, and cognitive impairment.

According to the Alzheimer’s Association, more than 5.7 million individuals worldwide have Alzheimer’s disease, with the number expected to rise to 14 million by 2050. By 2050, that number is predicted to rise to 16 million. The yearly expense of out-of-pocket healthcare for Alzheimer’s disease exceeds $250 billion.

Understanding the pathology

Vascular disorders of the heart and blood arteries are among the risk factors for Alzheimer’s disease. While certain risk factors are well-known, like age, others, such as brain cholesterol, are crucial in understanding how the disease progresses.

Brain cells interact through cholesterol-rich cell membranes, which is a natural mechanism that is required for proper brain function. According to studies, the brain contains between 23–25% of the body’s cholesterol.

Cholesterol accumulates in the brain and causes damage to the neuron—it’s long been understood as playing a role in Alzheimer’s disease pathology. However, what causes the cholesterol accumulation in the brain continues to be unknown and could hold answers.”

Xin Qi, Professor of Physiology and Biophysics, School of Medicine, Case Western Reserve University

The study

The study, ATAD3A oligomerization increases neuropathology and cognitive impairments in Alzheimer’s disease models, is the culmination of more than five years of research on the role of brain cholesterol and its link with Alzheimer’s disease.

The study’s goal was to answer two primary questions:

  • What function does cholesterol in the brain play in the disease?
  • How may this novel therapy approach be employed in the future?

The study focused on the protein-coding gene ATAD3A, according to Qi, the paper’s senior author. There are a lot of researchers who do not know how the protein works in neurodegenerative diseases.

In Huntington’s disease, the molecule ATAD3A becomes hyperactive and is oligomerized (repeated), which is a cause of the disease. We worked with data scientists to see if ATAD3A also has a link to Alzheimer’s disease and, to our surprise, we found that the molecule is a top candidate linked to Alzheimer’s.”

Xin Qi, Professor, Physiology and Biophysics, School of Medicine, Case Western Reserve University

Researchers then used models to gather data and discovered a relationship between ATAD3A and brain cholesterol. ATAD3A inhibits another protein called CYP46A1 after it produces repeated similar or identical portions through a process called oligomerization, according to the researchers.

Because the new protein inhibits cholesterol from being processed in the brain, it builds up. The increase in brain cholesterol has been related to disease development in neurodegenerative diseases, according to researchers.

The findings

The results indicate that ATAD3A, particularly during oligomerization, may have a role in the development of Alzheimer’s disease.

Qi says that as now a probable target has been found, the next step in treatment will be peptide inhibitors, which bind to ATAD3A and stop it from working.

Models treated with the peptide showed improved performance on the memory tests. They showed increased memory retention, stronger cognitive activity and up to 50% restored damage to the memory.”

Xin Qi, Professor of Physiology and Biophysics, School of Medicine, Case Western Reserve University

According to Qi, addressing ATAD3A oligomerization might potentially decrease the course of Alzheimer’s disease. More testing is being carried out.

Source:
Journal reference:

Zhao, Y., et al. (2022) ATAD3A oligomerization promotes neuropathology and cognitive deficits in Alzheimer’s disease models. Nature Communications. doi.org/10.1038/s41467-022-28769-9.

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