Thanks to the monoclonal antibody "12A12" an all-Italian research has shown that its administration can bring significant improvements in the main alterations produced by Alzheimer's disease.
Alzheimer's disease
Alzheimer's is the most common of dementias: it is a neurodegenerative disease, initially gradual and silent, which destroys brain cells. The numbers are constantly growing: it is now a real pandemic for people over 80; in that age group, in fact, about one third suffers from dementia. The number of patients increases every year, with very heavy economic and social consequences: there are forty million all over the world, over ten million in Europe and over a million in Italy. It is estimated that in the old continent the total cost of dementia is 789 billion euros per year.
Despite the great commitment of science and researchers on a global level, to date there is no definitive cure, and the causes themselves are not yet fully known. Alzheimer's is a complex disease, probably triggered by a set of risk factors.
Among the main neuropathological processes responsible for Alzheimer's disease, the alteration of the Tau protein is of great importance, which tends to accumulate in the brains of patients, increasing as the disease progresses.
Alzheimer's: Italian research with monoclonal antibody
A recent Italian scientific study coordinated by Dr. Giuseppina Amadoro and Dr. Roberto Coccurello used a monoclonal antibody, called "12A12", and demonstrated that its administration can bring "significant improvements" in the main alterations produced by Alzheimer's disease.
This study was coordinated byInstitute of Translational Pharmacology (Ift) e by the Institute of Complex Systems (Isc) of the National Research Council (Cnr) - with whom they collaborated the Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (Cnr-Ibiom), there S. Lucia Foundation (a scientific hospitalization and treatment institute, i.e. an Irccs), the Ebri Foundation, the A. Gemelli University Hospital and theIrccs Bietti Foundation.
We interviewed the dr. Roberto Coccurello, a neuroscientist of the S. Lucia Foundation and of the Institute of Complex Systems of the CNR, to understand more about this pathology and to tell us in detail what results the study reached.
Let's start from the beginning: what is Alzheimer's and how does the disease evolve?
This is an important question, however the answer is particularly complex. Answering what exactly Alzheimer's disease is would mean having fully understood its multiple causes and therefore its etiology and pathophysiology. And this is not entirely clear to any of us today. We can say that Alzheimer's is the absolute form of dementia with the highest incidence of cases in the general population.
Being a dementia, a slow progressive disease, linked to pathological aging, it is characterized by the deterioration of the cognitive functions of the mind and thinking, first of all those related to the different types of memory but also of learning, of verbal expression, conceptual, focused attention.
Alzheimer's disease affects the central nervous system and progressively the loss of its main components, that is, its information processing units, which are our nerve cells, our neurons. The progressive loss of neurons is attributable to the formation of non-soluble proteins that form the so-called plaques, which we often hear about, the beta-amyloid protein plaques, but also alterations of the Tau protein. The Tau protein in fact undergoes alterations that damage the cellular structure, with free Tau proteins that form deposits, aggregates, which are called neurofibrillary tangles, which lead to death and necrosis of brain cells. The damage caused by Alzheimer's to the central nervous system is deep and complex, not only limited to neurons but also affects the immune cells of our nervous system, which play a vital role in brain surveillance, immune surveillance. Unfortunately, the immune cells that initially intervene to protect neurons attacked by the beta-amyloid protein and the neurofibrillar tangles of the Tau protein can, in the meantime, favor inflammation and the progression of the disease, indiscriminately affecting healthy neurons and neurons where they are. present amyloid plaques. The disease tends to worsen over time and for this reason it falls into the clinical-diagnostic category of neuro-degenerative diseases.
An initial phase can be distinguished, free from disability and manifest symptoms, followed by mild cognitive decline, then moderate decline, with deterioration of personal, autobiographical and even recent events memories, as well as changes in character or mood in social contexts. In the subsequent phases we can first observe a moderately severe cognitive decline, which corresponds to the intermediate phase, lasting between two and ten years, followed by a more severe cognitive decline, i.e. a severe phase lasting an average of three years, which is followed by a terminal phase, shorter, between six and twelve months. These last three stages mark the transition from symptoms such as not being able to remember one's address, phone number, high school attended, or loss of awareness of more recent experiences, difficulty to remember the name of the spouse, finally also to lose the ability to respond to one's environment, to carry on a conversation, to control movements.
The causes of the disease are not fully known, but it is known that a role is played by the Tau protein. But how does it act in the onset and then in the progression of Alzheimer's disease?
Alzheimer's recognizes the presence of a specific alteration of the Tau protein, alterations that damage the cellular structure, with free proteins that form aggregates, deposits, neurofibrillary tangles, which lead to the death of brain cells.
The Tau protein contributes - it is important - to form the skeleton of neurons, which is called the cytoskeleton, and to stabilize the structure and shape of the cells of the brain, but also to facilitate the expulsion of toxic substances from nerve cells. According to recent studies, the Tau protein undergoes changes in shape, therefore morphological, and functions, which change over time; consequently, scientific attention has turned more to the development of drugs against the Tau protein and much less towards molecules and drugs aimed at reducing the accumulation of beta - amyloid protein that we talked about earlier.
An important aspect is that in Alzheimer's the protein Tau it presents itself in a different way in the different stages of the disease, in particular it has been observed that it undergoes biochemical changes that correlate, that is, they follow over time, the severity and development of the disease. To understand the etiology, that is the causes of Alzheimer's, we must identify the neuro-biological alterations from the earliest stages of their appearance. These neurofibrillary tangles formed by altered Tau, for example, have been observed as early neuro-pathological changes in Alzheimer's in certain regions of the brain.
As in an area of the cerebral cortex called the entorhinal cortex. Currently it is scientifically accredited and accepted the idea that the alterations of the conformations of Tau occur precociously during the development of the disease, even before the Tau itself degenerates into those tangles we have talked about so far. It is also accepted that these changes in shape and conformation go hand in hand with, and correlate with, the severity of dementia.
Use of a new monoclonal antibody in the Italian scientific study
What results have you achieved with your study? How does the 12A12 monoclonal antibody work?
Before answering about our antibody 12A12 I think it is good to spend a few words to clarify what we mean by monoclonal antibodies, especially in light of the fact that due to the Covid-19 pandemic there has been a lot of talk about these therapeutic tools, with little clarity. . Very schematically, I would say that an antibody is an immunoglobulin, that is a protein produced by B lymphocytes, a type of white blood cell capable of recognizing and neutralizing a molecule foreign to the organism called an antigen. The antigen is recognized thanks to the form taken by the antibodies which then bind selectively to its different regions.
This response is general of the immune system and is called polyclonal, because many types of antibodies are produced simultaneously by our body to attack different parts of the antigen. On the contrary, monoclonal antibodies are molecules produced in the synthesis laboratory and obtained from a single clone, therefore all the same and selective. They are obtained in particular with the fusion of a cell, the B lymphocyte extracted from the spleen, which produces antibodies for a certain target with cells cultured in isolation, from which identical clones are extracted and which are therefore defined as monoclonal antibodies.
In our recent scientific study we used the monoclonal antibody we call 12A12 as a possible immunotherapy in Alzheimer's disease. Regarding the question of how it works, it should be noted that this antibody has a very high specificity for a toxic fragment that is generated only in the pathological Tau protein present in Alzheimer's disease, a neurotoxic fragment. We tested the 12A12 antibody in a non-hereditary animal model of Alzheimer's disease, the most frequent form of the disease, and therefore in a model that has no inherited basis across generations. The antibody has been shown to be effective in neutralizing alterations in the metabolism of the Tau protein by acting exclusively against a peptite, a neurotoxic fragment that is generated in pathological Tau, which also particularly alters an organelle of nerve cells called mitochondrion. This means that this monoclonal antibody acts against a fragment that exists only in the altered Tau form in the brain of patients, and therefore cannot modify the physiology of the non-pathological Tau protein in the least. The administration, therefore, presents an important degree of safety for the patient and the organism. These results have previously been obtained on animal models including genetic ones and now on models, as I said, non-genetic of the disease, on animals that have pathophysiological characteristics that summarize when observed in the Alzheimer's patient. In our study we administered the 12A12 antibody for three weeks and demonstrated the possibility of inducing a recovery of cognitive deficits of different types of memory, as well as a reduction in the accumulation of that beta-amyloid protein in the brain we talked about earlier. The administration of the antibody then favored some repair processes both at the level of the mitochondria and at the level of oxidative stress present in the neurons. Being an animal model that simulates Alzheimer's disease through the administration of a toxin which in turn induces diabetes, the antibody has also made it possible to recover the function of some mechanisms related to the action of insulin in the brain. This is because the risk of developing Alzheimer's is much higher in people with diabetes, who have a deficit in the use of glucose in the brain. Therefore, the results confirmed the efficacy of the antibody that we had previously observed in genetic models also in the non-genetic model, with the diabetic toxin simulating some mechanisms present in the pathophysiology of the disease.
It is not the first time that monoclonal antibodies have been associated with Alzheimer's disease. In the United States, a few months ago, the American drug agency recently approved the use of the monoclonal antibody, Aducanumab, for patients with early Alzheimer's. What do you think?
True, this is not the first time that data has been presented or claimed to have tried the clinical use of monoclonal antibodies against Alzheimer's.
In addition to Aducanumab, for example, Gantenerumab is also a similar antibody directed against the formation and accumulation of the insoluble, non-soluble beta-amyloid protein, which gives rise to what are known to the public as amyloid plaques. However, the approval of Aducanumab was accompanied by some doubts regarding the results and safety during the clinical trial phases. This antibody, in phase 3 of experimentation, that is to say that of evaluating the efficacy of a compound, has in fact given rise to positive results in terms of slowing down cognitive decline, but in another study to no improvement. So it has a too variable efficacy, too controversial, there have also been cases of cerebral edema and lesions of an inflammatory and haemorrhagic nature. Indeed, due to concerns regarding the safety of Aducanumab, the European Medicines Agency has not given consent to approve this antibody in the European Union. However, this does not alter the fact that this is the right direction, namely that of a therapeutic approach aimed at the development of precision drugs capable of altering the processes, the mechanisms underlying the disease, responsible for its development and its pathogenesis. Accumulations of beta-amyloid can precede the onset of the first clinical symptoms by up to ten years and therefore be invisible. Beta amyloid always represents one of the mechanisms that trigger neurodegeneration together with inflammatory processes and the alteration of the Tau protein, which we attacked with our antibody, which is precisely at the center of our studies and scientific objectives.
In what future direction is your research heading? What objectives?
Our latest studies have confirmed the pathogenetic role of the Tau protein and with this also the importance that its neutralization and the neutralization of one of its toxic fragments for neurons can have for the development of a therapy. In fact, effective therapy also has as its primary objective to ensure patient safety, so we can imagine improving our understanding of the pathology of Alzheimer's, where cognitive decline and metabolic disorders linked to the action of insulin coexist.
The next study objectives will be directed on many different fronts, such as the investigation of the inflammatory components of the brain associated with the development of Alzheimer's, its origin and its immune component. Furthermore, we will investigate the role of retinal degeneration of the optic nerve, non-cerebral anatomical areas that can however signal the development of the pathology early. In parallel, we are addressing the role of the intestinal microbiota, that real super organism that we host in our intestines and with which we live. It is made up of more than 100 billion bacteria and is in direct communication with our brain. It therefore influences the regulation of various physiological but also pathological physiological functions, including Alzheimer's. The microbiota is profoundly altered in neurodegenerative diseases and it will be our aim to better understand this mechanism.
Studies like this fuel the hopes of millions of patients around the world. But how far are we, in your opinion, from having a definitive and effective therapy, or at least in slowing down Alzheimer's?
This is a question that perhaps none of the neuroscientists currently engaged in researching the mechanisms underlying this pathology would ever want to hear. There cannot be a single cure and a definitive therapy for this disease. On the other hand, we need many advanced therapeutic tools, because this disease is multifactorial, has many causes and is variable in its evolution for individual subjects.
We need strategies that allow us to attack some of the mechanisms that we have learned about in recent years of study, including those of the neuro-inflammatory type, which in turn have a multiple etiology. Indeed, it will be more plausible to slow down the tragic and disabling progression of the disease with integrated approaches of innovative drugs, such as monoclonal antibodies, and neuro rehabilitation support. But I would also say a new attention to the patient's nutrition, especially in the early stages of onset and development of cognitive disability.
With regard to the need for an integrated approach, to care and research, I would like to conclude by spending a few words on the environmental and professional context in which our studies take place and have been carried out. This is a very important aspect to have the opportunity to obtain encouraging results. These studies were carried out in collaboration with the Institute of complex systems of the CNR, to which I belong, and my colleague Dr. Giuseppina Amadoro of the Institute of Translational Pharmacology, also of the CNR, who followed the debut, the history, the development of the antibody 12A12. The working context is a scientifically valid environment, as far as I'm concerned it is the Santa Lucia Foundation, which is a scientific hospitalization and treatment institute, in Italy they are called Irccs, which is also the first Italian Irccs for neuroscience. Without the support of this scientific network there would not even have been the possibility of obtaining encouraging results. Results that confirm neuroprotective effects of the 12A12 antibody both in genetic models and in diabetic Alzheimer's models and that can trace a route, a path, for the passage to the phase 1 clinical trial on humans.
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