Scientists Discover Promising Molecule That Restores Cognitive Function in Early Alzheimer’s
By University of the Basque CountryJanuary 25, 2025 -- 22 Comments
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A study by the University of the Basque Country (UPV/EHU) demonstrates that the drug WIN55,212-2 protects the brain and reverses early cognitive damage caused by dementia, while also explaining its mechanism of action.
Over two decades of research conducted by the Neurochemistry and Neurodegeneration group at UPV/EHU, led by Dr. Rafael Rodríguez-Puertas, has uncovered a promising pathway for developing therapies aimed at improving memory in cases of cognitive impairment caused by neurodegenerative diseases like Alzheimer’s;
Alzheimer disease is a progressive neurological disorder that primarily affects older adults, leading to memory loss, cognitive decline, and behavioral changes. It is the most common cause of dementia. The disease is characterized by the buildup of amyloid plaques and tau tangles in the brain, which disrupt cell function and communication. There is currently no cure, and treatments focus on managing symptoms and improving quality of life.
Alzheimer’s and Parkinson’s.
A study by Dr. Marta Moreno-Rodríguez within the group demonstrated that cannabinoid neurotransmitter
A neurotransmitter is a chemical substance that transmits signals across a synapse from one neuron to another in the nervous system. These chemicals play a crucial role in the functioning of the brain and body, influencing everything from mood, sleep, and learning to heart rate, anxiety, and fear. Common neurotransmitters include dopamine, serotonin, acetylcholine, and norepinephrine. They bind to specific receptors on the surface of neurons, triggering various physiological responses and allowing for the communication that underpins all neural activities. Imbalances in neurotransmitter levels can lead to neurological disorders or mental health issues, making them a central focus of study in both medicine and psychology. Neurotransmitter receptors and specific choline-containing lipids in the brain play a role in enhancing cognitive function in rats.
The researcher Rodríguez-Puertas explained that “analyses carried out over the years on a very large sample of brain tissue from autopsies of patients who were at different stages of development of the disease enabled us, intriguingly, to see that when the first clinical symptoms of Alzheimer’s emerge, damage is found in the area that is initially affected in patients and is caused by one of the interneuronal transmission systems, the cholinergic system (which controls memory and learning and uses acetylcholine.
Acetylcholine is a neurotransmitter that is essential for many functions in both the central and peripheral nervous systems. In the peripheral nervous system, acetylcholine activates muscles and is a major part of the autonomic nervous system, influencing activities such as muscle contraction, heart rate, digestion, and dilation of blood vessels. In the central nervous system, it plays a role in arousal, attention, memory, and motivation. Acetylcholine is also involved in the promotion of rapid eye movement (REM) sleep. Disruptions in acetylcholine production can contribute to neurological conditions, such as Alzheimer's disease, where there is a noted decrease in acetylcholine concentrations in certain parts of the brain. (acetylcholine as a neurotransmitter); by contrast, we saw that another neurotransmission system, the cannabinoid system, increases.”
The team also found that as the disease progresses, the cannabinoid system also ends up damaged: “It’s as if this cannabinoid system has an initial protective response to the damage of the cholinergic system and tries to protect the brain,” he said. “It is therefore a therapeutic target on which to act.”
From left to right, Gorka Pereira, Marta Moreno, Ivan Manuel, Rafael Rodriguez-Puertas, Alberto Llorente and Jonatan Martinez. Credit: Laura López. UPV/EHU.
A novel technique to identify and locate lipids in the brain
The research group was able to understand the mechanism of this cognitive improvement “by using a novel technique developed and fine-tuned by the research group at the UPV/EHU and which enables the lipids in the brain to be identified and anatomically located. That way we saw that, after treatment, the activity of the cannabinoid system had increased; and also that there was an increase in the activity of the patients’ cholinergic neuronal receptors that had been damaged, and also that there was an increase in the synthesis of certain lipids containing choline, which are precursors of acetylcholine, a neurotransmitter that controls memory and learning in the brain,” explained Rafael Rodríguez.In other words, “the cannabinoid receptors were seen to be activated and the acetylcholine levels in the brain to be increased. The drug restored the cholinergic system and improved memory,” added Moreno.
Rafael Rodríguez believes that “this molecule could become a drug to treat the symptoms of dementia, at least during the initial stages of the disease, because we have already seen that the body itself, physiologically, tries to do something similar.”
“With these pharmacological treatments we could help to enhance that effect, or perhaps even apply a mixed treatment of cannabinoid drugs with acetylcholine precursors,” he suggested.
Seeking similar molecules to move on to clinical trials
Although the results of the tests on rodents were very promising, and the next step would be to study their toxicity and move on to clinical testing on humans, the research team has come up against the obstacle that the molecule is a free-to-use molecule.In other words “it is a synthesis molecule that is widely used in experimentation; we did not synthesize it ourselves. It is not a molecule that a particular pharmaceutical company can exploit. Toxicology studies and clinical trials constitute a major investment for the pharmaceutical industry and this molecule does not offer them the possibility of future commercial exploitation”; so they are now working to find and synthesize molecules similar to WIN55.212-2 that could be of interest to the pharmaceutical industry and thus pave the way towards the clinical study of this new therapeutic pathway.
To this end, they are working in collaboration with CIC bioGUNE and the University of Vigo.
Additional information
This study is the outcome of many years of uninterrupted work and of the PhD thesis of the researcher Marta Moreno-Rodríguez, written up under the supervision of Rafael Rodríguez-Puertas, a tenured doctoral researcher and leader of the UPV/EHU’s Neurochemistry and Neurodegeneration research group. Marta Moreno is currently working at the Barrow Neurological Institute in Arizona (USA).The tissue samples analyzed over the years came from the Basque Biobank, the Central University Hospital of Asturias, and the Barrow Neurological Institute (USA).
Reference: “Cognitive improvement via cortical cannabinoid receptors and choline-containing lipids” by Marta Moreno-Rodríguez, Jonatan Martínez-Gardeazabal, Iker Bengoetxea de Tena, Alberto Llorente-Ovejero, Laura Lombardero, Estibaliz González de San Román, Lydia Giménez-Llort, Iván Manuel and Rafael Rodríguez-Puertas, 3 November 2024, British Journal of Pharmacology.
DOI: 10.1111/bph.17381
