Alzheimer’s Disease International estimated that in 2020, more than 55 million people worldwide were living with Alzheimer’s. It is anticipated that this number will nearly double every 20 years, reaching 78 million in 2030 and 139 million in 2050. In 2021, the WHO Global Status Report stated that the yearly global cost of dementia was over $1.3 trillion, and by 2030, this number is projected to increase to $2.8 trillion.
As per Neuroscience News, the failure of the majority of Alzheimer’s disease treatments to date is largely attributable to the fact that they target the wrong biomarkers and patients who already exhibit symptoms of the disease. Once symptoms show, however, it is likely that many brain cells crucial for memory and cognition are irreparably damaged.
Professor Shai Rahimipour of the Chemistry Department at Bar-Ilan University in Israel has pioneered the use of theranostics to identify and treat the early, pre-symptomatic indications of Alzheimer’s disease. The scientific community has paid close attention to Rahimipour’s innovative method because of its potential to halt the advancement of the disease prior to the commencement of irreparable brain cell destruction. In Alzheimer’s disease, a tiny protein known as amyloid beta misfolds into intermediates that aggregate into fibrils and plaques, which are larger macromolecular structures.
Because plaques are observable under a microscope, scientists have long suspected they are responsible for neuronal damage in the genesis of Alzheimer’s disease. Over the course of more than a quarter century, numerous clinical trials and billions of dollars were invested to develop chemicals and antibodies that target and prevent the production of fibrils and plaques. These treatments were ineffective and induced terrible adverse effects.
Over time, fibrils and plaques were declared non-toxic, and today soluble intermediates known as oligomers are believed to be the cause of this insidious disease. Recent therapeutic trials using antibodies to target oligomers have shown encouraging outcomes, and the US Food and Drug Administration (FDA) has approved the Biogen/Essai antibodies Aducanumab and Lecanemab.
Microhemorrhages and brain swelling are illustrative of the need for improved therapies and diagnostic techniques for early Alzheimer’s disease identification in order to raise the quality of treatment. In addition, the blood-brain barrier inhibits the penetration of proteins and antibodies, preventing the majority of antibodies from reaching the brain.
Rahimipour and his team have solved these obstacles by creating tiny abiotic and druggable cyclic peptides that have demonstrated efficacy in animal models for identifying the pre-symptomatic early stage of Alzheimer’s and treating the illness by targeting oligomers. When these molecules were mixed with the tiny protein amyloid beta in a test tube, the formation of oligomers was totally inhibited, and no subsequent aggregation occurred.
In the following step, the hazardous oligomers and cyclic peptides were incubated with human neurons. The majority of neurons survived, whereas those in the control group exposed to oligomers without cyclic peptides were badly injured and died. Next, they examined the effectiveness of the cyclic peptides in transgenic C. elegans worms that acquire Alzheimer’s-like symptoms.
The researchers observed that feeding the worms cyclic peptides significantly prolonged their survival and eradicated the disease by preventing the formation of early toxic oligomers, indicating that the aggregation process can be halted in the earliest stages of the disease, even before oligomers are formed.
The researchers next evaluated transgenic mice with a radioactive form of the cyclic peptides in order to get a pre-symptomatic diagnosis using Positron Emission Tomography (PET), a hospital-standard procedure.
To the researchers’ delight, the molecule detected for the first time early amyloid beta oligomers in the thalamus (which transmits motor and sensory information to the cerebral cortex) of pre-symptomatic animals prior to their spread to other brain regions.
The presymptomatic transgenic mice were then treated with cyclic peptides, and their memory functions and brain amyloid beta oligomer levels were monitored throughout time. The researchers determined through molecular imaging that the mice did not produce considerable amounts of oligomers and, thus, did not acquire Alzheimer’s.
“In these animal models, we have effectively stopped the disease in its early stages, even before the formation of oligomers. Prof. Rahimipour explains that one of the greatest advantages of our synthetic molecules, in contrast to natural antibodies, is that they are not immunogenic and remain in the body for a considerably longer period of time, so fewer injections or applications will likely be required.
“Our thorough trials have revealed no toxicity, and, unlike antibodies, the molecules are able to traverse the blood-brain barrier with ease,” he says. The recent publication of Professor Rahimipour’s study in the Proceedings of the National Academy of Sciences was accomplished in conjunction with Canadian colleagues from the Université de Sherbrooke and the Université de Montréal. Currently, he is developing an appropriate medicine for pre-clinical and clinical testing.
