Claudia Villalobos
The brain is the most complex organ in the human body. It is composed of around 100 billion nerve cells (neurons) that communicate through electrochemical signals, with trillions of synapses and 1 million kilometers of interconnected fibers. It serves as the control center involved in memory, thoughts, speech, movement, and regulates the function of many organs. Although it functions rapidly and automatically in healthy individuals, certain diseases can affect its functions.
When someone suffers from Alzheimer's disease, the brain undergoes alterations that gradually lead to the loss of memory, thinking abilities, social skills, and behavioral changes. Due to the lack of a cure for this disease, which gradually diminishes patients' ability to be self-sufficient, engage in conversations with others, and recognize themselves and their loved ones, scientists from around the world, including those from the Instituto Politécnico Nacional (IPN), are studying the mechanisms involved in the dysregulated production of proteins. They are also searching for early diagnoses and treatments to help preserve memories.
The stages of this dementia occur gradually, much like if cracks were to gradually appear in asphalt, which would turn into increasingly larger fissures that, despite people's efforts to avoid them, would inevitably open up on the path and lead them into a dark passage. In this passage, amid confusion and sometimes with faint glimmers of light, they wander aimlessly in search of words and experiences that are slowly fading away.
By viewing humans as holistic beings, scientists from the National School of Biological Sciences (ENCB) have established collaboration with the National Dementia Biobank (BND) to promote holistic research on Alzheimer's disease. The goal is to extend studies beyond etiological, physiological, and neuropathological aspects to include the emotions of patients.
Like other neurodegenerative diseases, Alzheimer's is exclusive to humans, making it impossible to reproduce it in any animal model. For example, certain proteins involved in this condition can be expressed in mice, but the molecular process is completely different.
Therefore, the study of this neuropathology must be conducted directly on human brains. "To facilitate research, it is important to raise awareness and promote brain donation, both from diseased individuals and healthy individuals, in order to have a basis for comparison," warned Dr. José Luna Muñoz, Director General of the BND, who has been focused on unraveling the mechanisms underlying this disease for over 25 years. It is estimated that Alzheimer's affects 1.6 million people in Mexico, a number that is expected to significantly increase due to population aging.
Thanks to this collaboration, undergraduate and graduate students from the IPN and other educational institutions actively participate in studying the risk factors that contribute to the disease (such as diabetes, hypertension, alcoholism, drug addiction, and the conditions generated by the SARS-CoV-2 virus in the central nervous system), the proteins involved in neuronal death, and the relationship between emotions and the disease.
"All the aspects we address focus on a specific point: finding a biomarker and a non-invasive method for the early and specific diagnosis of Alzheimer's disease, in order to differentiate it from other conditions that cause memory impairments," emphasized Dr. Luna Muñoz. The embryonic origin of the oral epithelium is very similar to that of the brain. Due to this similarity, experiments have been conducted using oral samples with very promising results, making it feasible to take samples from the oral cavity for early diagnosis.
"Initially, it was believed that Tau protein was exclusive to the nervous system, but we have found that it is also present in a constitutive form with other functions that were not described in other organs. That's why, at the BND, we also have other tissues such as skin, pancreas, kidney, intestine, and liver to further our research," highlighted the scientist affiliated with the National Researchers System, Level II.
In addition, they found two proteins that have not been described in the scientific literature for Alzheimer's disease, one of which is associated with amyloid-beta protein deposits, which generate a severe inflammatory process in the central nervous system of patients. The other is the alternative splicing factor protein (splicing), which correlates with the evolutionary process of the disease.
Given the lack of a cure for Alzheimer's, certain drugs are currently used to slow down the progression of the disease. In this process, managing the emotions of patients is crucial. That's why the research conducted at the Polytechnic Institute also involves studying emotions and their relationship with this dementia.
"In addition to studying cognitive decline, our research also incorporates the analysis of emotions in the progression of the disease. Therefore, we also study changes in the amygdala, cingulate cortex, and hippocampus, which are brain areas associated with emotions," Luna Muñoz explained.
Scientists from the ENCB, Fidel de la Cruz López, Linda Garcés Ramírez, and doctoral student Ricardo Apátiga Pérez, who is currently conducting research at the Research Unit in Glycobiology, Cell Growth, and Tissue Repair (Gly-CRRET) at the University Paris Est Créteil, are involved in this task. They are analyzing the presence of lesions (neurofibrillary tangles and amyloid plaques) in the hippocampus and compare them with those found in the cingulate cortex and amygdala. "These studies will have a direct implication for clinicians, but it will also be important for them to consider the aspect of emotions in their diagnoses." Dr. Luna emphasized that there is also a collaboration with neuropsychologist Ninoska Ocampo Barba from the Institute of Behavioral Neuroscience at the Autonomous University "Gabriel René Moreno" in Bolivia, who will support the training of Mexican gerontologists and psychologists in the field of neurostimulation so that they can provide care and support to patients and their families in the course of the disease and brain donation for research purposes.
The BND safeguards 15 complete brains, as well as approximately 400 fragments of the hippocampus, temporal cortex, frontal cortex, cingulate cortex, and cerebellum. They have tissue samples from Alzheimer's disease, frontotemporal dementia, corticobasal dementia, progressive supranuclear palsy, Parkinson's disease, Pick's disease, Lewy bodies, and COVID-19.
Dr. Fidel de la Cruz López, who has studied fear for over five decades, highlighted the importance of incorporating emotions as an integral part of Alzheimer's research. "When a person knows they are sick, they experience a fear reaction to the idea that their body may no longer function properly or that they may lose their life. This sensation feeds into behavioral and cognitive transformation; emotionally, there are a series of alterations that can lead to depression, so their study is necessary."
As part of the experimental approach, they observe how this affects the limbic system in the brain, which is considered the "emotional brain" because its functions are related to the emergence and regulation of emotions and bodily responses. "Our expectations are high. The knowledge derived from this research will allow us to provide more targeted support that goes beyond, to understand how the patient feels and try to modify that feeling," he explained.
Chaperone proteins are present in all cells and their function is to modulate the activity of other proteins. In turn, Sigma chaperone proteins play a role in the activity of certain neurotransmitters, including acetylcholine, which is involved in memory, learning, and concentration, and its levels are low in people with Alzheimer's.
In addition to studying emotions and their relationship with this disease, Dr. Linda Garcés Ramírez analyzes the marking of these proteins in the brains and their implications in the development of processes involved in Alzheimer's.
Alzheimer in Mexico affects 1.6 million people, a number that is expected to increase due to population aging.
The polytechnic researcher gained experience in the analysis of Sigma chaperone proteins during a doctoral stay at the National Institutes of Health in the United States, in Baltimore. She will apply the acquired knowledge to find answers regarding this condition.
The impact that research generated at the Instituto Politécnico Nacional has worldwide is becoming increasingly evident. This international projection of knowledge is largely due to the cutting-edge education received by students in classrooms, but above all, to the fact that scientists involve them in the generation of this new knowledge. Dr. Rocío Ortiz Butrón is one of the professors at the ENCB who participates in this arduous task.
The weight of a healthy adult brain is between 1,400 and 1,600 grams, while that of someone with advanced Alzheimer's is as low as 600 grams and can fit in the palm of your hand?
Epigenetics (external factors such as exercise, healthy diet, and sufficient rest) can delay the onset of the disease or influence its progression to be slower?
The love and support of family and friends can help control emotions such as fear and depression, which are often experienced by patients?
You can donate your brain or that of a family member to support the comprehensive research of Alzheimer's disease conducted by the Instituto Politécnico Nacional and the National Dementia Biobank?
"In addition to the theoretical explanation of the physiological process at the neuronal level, students now have the challenge of experimentation, which they can carry out thanks to the collaboration with the National Dementia Biobank."
Currently, three master's students and four doctoral students are conducting their thesis work directly analyzing brains. They observe and study the alterations that occur with Alzheimer's. "For example, they analyze neurofibrillary tangles formed by the accumulation of Tau protein," Ortiz Butrón warned.
"Neurons have structures inside them called microtubules, which transport neurotransmitters to the end of the neuron to act on the receptor of another neuron. These microtubules are assembled by the Tau protein, which gives them firmness, but if it is highly phosphorylated - as is the case in Alzheimer's disease - the microtubules lose firmness, Tau protein accumulates, and neurofibrillary tangles or filaments are formed, leading to neuronal death," emphasized the scientist.
According to the latest advances, the professor is confident that the results obtained from this line of research will be very promising. Although scientific progress is slow, the study of the human brain opens up new possibilities for generating cutting-edge knowledge and training young scientists whose findings will transcend borders.
As research progresses, the challenges increase because Alzheimer's disease is very complex. However, a significant aspect is the growing collaborations, the scientific exchange with researchers from different countries and with other brain banks in Latin America, such as those in Colombia, Argentina, Brazil, and the Dominican Republic. All scientists focus their efforts on the same goal: promoting brain donation, giving "new life to the brain," and preventing memories from fading away.
The early exposure to science shaped the life of Master of Science Nabil Itzi Luna Viramontes, who chose the meticulous and challenging task of exploring the intricacies of the human brain, driven by her love for others and the commitment to finding answers that lead to early diagnostic methods for Alzheimer's disease.
"I was always involved in scientific work because my father used to take me to the laboratory with him. I remember being four years old when I saw a human brain for the first time. He would explain the procedures he was conducting, and I listened to his presentations with great interest."
Years later, the young scientist was involved in staining techniques and accompanied Dr. José Luna Muñoz to give talks in different forums about Alzheimer's disease and the importance of brain donation for its study. "The contact with patients allowed me to strengthen my passion for developing science to help the sick."
She studied a bachelor's degree in Experimental Biology at the Universidad Autónoma Metropolitana (UAM). Subsequently, under her father's guidance, she obtained a Master's degree in Biological Sciences at the Escuela Nacional de Ciencias Biológicas (ENCB), IPN. Now, she is focusing her doctoral thesis on studying the relationship between the splicing factor and Tau protein, which is unprecedented research worldwide.
"Normally, all cells undergo splicing (a process that allows the expression of multiple isoforms of the same protein from a single gene) for proper cellular functioning. The splicing factor protein should only be found in speckles (small structures located in the nucleus of neurons). However, in Alzheimer's disease, it is not present in the nucleus but remains in the cytoplasm and has a close association with the Tau protein."
To assess whether this alteration occurs in the early stages of the formation of various Tau proteins with different lengths, Ms. Luna Viramontes is searching for mechanisms and proteins that regulate their synthesis.
The Deputy Director of the National Dementia Biobank emphasized that if it is proven that Tau protein is produced not only in the brain but also in other tissues, it will be evaluated if it is feasible to obtain it from buccal epithelium to verify the splicing factor dysregulation and have an early diagnostic method.
With a friendly tone and serene gaze, Ms. Nabil Itzi takes pride in being part of a high-level research group and maintains the confidence that advancements will offer a better quality of life to people suffering from Alzheimer's or any neurodegenerative disease. However, her main challenge, like any child, will be to surpass her father's scientific achievements, Dr. José Luna Muñoz.
Selección Gaceta Politécnica #162. 2023, May 31st. IPN Imagen Institucional: Read the full magazine in spanish here
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