Breakthrough New Treatment Developed for Alzheimer’s Disease

Professor Shai Rahimipoor of the Department of Chemistry, Bar-Ilan University, Israel, has taken a unique approach in pursuing drug treatments for Alzheimer’s disease. Rahimipour hopes to use theranostics to identify and treat the presymptomatic signs of the disease, thereby preventing the irreversible damage to brain cells that occurs as the disease progresses. His innovative approach holds promise in halting disease progression and has gained considerable recognition in the scientific community.

A new molecule developed by researchers at Bar-Ilan University has proven useful in diagnosis. Alzheimer’s disease It prevents the progression of the disease at its earliest stage, before the onset of symptoms.

According to Alzheimer’s Disease International, more than 55 million people worldwide had Alzheimer’s disease in 2020. This figure is expected to double nearly every 20 years, reaching 78 million in 2030 and 139 million in 2050.

To date, most drugs developed to treat Alzheimer’s disease have failed. The main reason is targeting the wrong biomarkers and individuals who are already showing signs of the disease. However, when symptoms appear, many brain cells responsible for memory and cognition have already been damaged and may not be repaired.

Professor Shai Rahimipour of the Department of Chemistry Bar-Ilan University Rahimipour’s breakthrough approach, which shows the potential to halt disease progression before irreversible brain cell damage occurs, has received a great deal of attention in the scientific community.

In Alzheimer’s disease, a small protein known as amyloid beta misfolds into intermediates that aggregate into larger macromolecular structures known as fibrils and plaques.

Because plaques can be seen under a microscope, scientists long believed they played a role in neuronal damage in the pathogenesis of Alzheimer’s disease. invested in generating molecules and antibodies that target and prevent fibril and plaque formation. Such treatments have failed and caused intolerable side effects. Over time, the fibrils and plaques themselves were considered non-toxic, and instead former soluble intermediates known as oligomers are now thought to be responsible for this insidious disease.

Recent clinical trials using oligomer-targeted antibodies have shown promising results, and the Biogen/Essai antibodies Aducanumab and Lecanemab have received U.S. Food and Drug Administration (FDA) approval. Controversy over efficacy and prominent side effects such as microhemorrhages and brain swelling highlight the need for better therapies and tools for early AD detection to improve standard of care. In addition, most antibodies do not reach the brain well because the blood-brain barrier limits the penetration of proteins and antibodies.

Rahimipour and his team have developed small, non-biologic drugs that have proven effective in diagnosing the early preclinical stages of Alzheimer’s disease in animal models and treating the disease by targeting oligomers. We overcame these barriers by developing a cyclizable cyclic peptide. When these molecules were combined with the small protein amyloid beta in vitro, oligomer formation was completely blocked and no subsequent aggregation occurred.

In the next step, researchers cultured human neurons with toxic oligomers and cyclic peptides. Most neurons remained alive, whereas neurons in the control group exposed to oligomers without cyclic peptides suffered severe damage and died.

Next, they tested the efficacy of cyclic peptides in transgenics. Nematode A worm that develops Alzheimer’s-like symptoms. The researchers observed that feeding worms with cyclic peptides dramatically prolonged worm survival and eliminated disease emergence by preventing the formation of early toxic oligomers. This suggests that aggregation processes can be stopped very early in the disease. , even before oligomers are formed.

The researchers then examined transgenic mice using a radioactive version of the cyclic peptide and obtained a presymptomatic diagnosis by positron emission tomography (PET), a technique commonly used in hospitals. rice field. Much to their delight, the molecule was found in the presymptomatic mouse thalamus, which relays motor and sensory signals to the cerebral cortex, to transport early amyloid-beta oligomers for the first time before diffusing to other brain sites. that we have detected.That is, they successfully predetermined the onset of the disease Before Amyloid fibril and plaque formation, and before symptoms of Alzheimer’s disease appear!

Next, we treated presymptomatic transgenic mice with cyclic peptides and monitored memory function and the amount of amyloid-beta oligomers in the brain over time. Through molecular imaging, the researchers confirmed that the mice did not produce substantial amounts of oligomers and, as a result, did not develop signs of Alzheimer’s disease.

“In these animal models, we effectively stopped the disease at an early stage, before oligomers were formed. It’s non-toxic and stays in the body much longer, so fewer injections or applications are needed,” says Professor Rahimipour. “Our rigorous regime showed no signs of toxicity, and unlike antibodies, the molecule crosses the blood-brain barrier very well,” he adds.

Professor Rahimipour’s research was recently published in a journal Proceedings of the National Academy of Sciences, in collaboration with colleagues from Sherbrooke University and the University of Montreal, Canada. He is currently working on developing drugs suitable for preclinical and clinical trials.

Reference: “Early Diagnosis and Treatment of Alzheimer’s Disease by Targeting Toxic Soluble Aβ Oligomers” Malam Habashi, Suresh Vutra, Kuldeep Tripathi, Sudipta Senapati, Pradeep S. Chauhan, Anat Haviv Chesner, Michal Richman, Samia Ait Mohand , Veronica Dumeuron-Perreault, Ramakotaiah Mulamreddy, Eitan Okun, Jordan H. Chill, Brigitte Guerin, William D. Lubell, Shai Rahimipour, 28 November 2022, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2210766119