It is because we have only a partial understanding of the molecular mechanisms of Alzheimer's disease that we have made little therapeutic progress concerning it, according to our partner
The Conversation
.
The hypothesis of an alteration in the distribution of “metals” in the brain, which could promote the degeneration and death of neurons, is a line of research.
This analysis was conducted by
Nicolas Vitale
, research director at the National Institute for Health and Medical Research (Inserm);
Christelle Hureau
, director of research at the National Center for Scientific Research (CNRS);
Michael Okafor
, PhD student at the Institute of Cellular and Integrative Neurosciences and the Institute of Chemistry of the University of Strasbourg;
Peter Faller
, professor of chemistry at the University of Strasbourg.
Neurodegenerative diseases are characterized by a progressive deterioration of neurons, leading to dysfunction of the nervous system and a gradual loss of cognitive and/or motor abilities.
Alzheimer's disease is the most common form of these pathologies.
Although the latter has a major societal impact and cost in our aging societies, very little progress has been made from a therapeutic point of view, despite significant efforts in clinical research.
This apparent paradox could come from a still partial understanding of its molecular mechanisms.
We are trying to shed original light on this subject here by focusing on the alteration of the distribution of "metals" in the brain, which could promote the degeneration and death of neurons.
For the sake of simplicity, we use the term "metals" to refer to metal ions derived from zinc Zn (II), copper Cu (I/II) and iron Fe (II/III).
An origin still misunderstood
As early as 1907, the original work of Alois Alzheimer had highlighted the existence of so-called "amyloid" plaques (deposit of aggregated proteins) in the brain of a deceased patient who had suffered from dementia characteristic of the disease which would later bear its name.
But more than a century later, many aspects of the disease remain in the shadows.
These amyloid plaques result from the aggregation of proteins called Amyloid-β (Aβ), identified by George Glenner and Caine Wong (University of California) in 1984, then from their accumulation.
Aggregation is the phenomenon by which they come together to form very stable sets.
Aβ proteins come from the cleavage of a longer, related protein called “amyloid precursor protein” (APP).
The functions of APP, like those of Aβ, still remain largely unknown and partially misunderstood.
The so-called "amyloid" theory that Alzheimer's disease is caused by the presence of these famous amyloid plaques in the brain was originally formulated by geneticist John Hardy (University College London) and neurobiologist Gerald Higgins (National Institute on Aging ) in 1992. But the real contribution of protein aggregates in the evolution of the disease remains today subject to debate.
Another theory is also formulated, this time implicating an abnormal intracellular aggregation of the Tau protein.
The latter, associated with microtubules (which participate in the formation of the cellular skeleton) and regulating their formation and deformation dynamics, can lead to fibrous tangles capable of spreading from one neuron to another and to the entire brain.
Usually, Tau receives a chemical group called phosphate in order to regulate its cellular functions.
However, under certain conditions, Tau is loaded with far too many phosphates, which will promote its aggregation and induce a loss of function and, ultimately, neuronal death.
These two theories, “amyloid” and “Tau”, have led to the development of numerous research projects for the development of drugs… which, for the time being, remain ineffective.
Many are in fact based on the use of transgenic (genetically modified) animal models or synthetic proteins that imperfectly reproduce human pathology.
Moreover, we now know that amyloid plaques can be present in the brain of patients who do not suffer from dementia and, conversely, be absent (or nearly so) in patients who have suffered from dementia.
In short, there does not seem to be a close correlation between the amount of amyloid plaques and the severity of the symptoms of the disease.
It therefore now seems important and urgent to consider Alzheimer's disease no longer under a single hypothesis, but to consider it under a multifactorial aspect.
Consider new approaches
One of the first arguments in favor of the multifactorial approach comes from genetic studies which have made it possible to highlight genes of susceptibility to the disease, that is to say genes whose variants can increase or decrease the risk of developing this disease. pathology.
The first and main one is the APOE gene variant 4 (APOE4) encoding apolipoprotein E (involved in lipid transport).
Since then, additional studies have made it possible to extend the number of genes whose variations are to be considered.
Interestingly, many relate to lipid metabolism, which could represent a complementary research axis to research on Aβ and Tau.
Among the additional hypotheses, we can also cite the dysfunctions of the neurotransmitter cycle, of the mitochondrial cascade, but also take into account pathologies such as diabetes, which are associated with an increased risk of developing the disease.
As we indicated in the preamble, our laboratories are working on a complementary hypothesis, still little studied in its therapeutic aspects, and which relates to an alteration in the regulation of metals.
Iron, copper and zinc are indeed all essential micronutrients for health; an imbalance in their concentrations in our body is incompatible with its proper functioning.
The metallic anomaly hypothesis
Our model is based on the observation of a change in the localization in the brain of certain metals, mainly zinc (Zn), iron (Fe) and copper (Cu), and on the fact that Aβ is able to bind to it, which promotes aggregation.
In addition, iron or copper bound to Aβ are also able to promote the production of reactive oxygen molecules, mainly free radicals, which are toxic if not lethal for neurons.
This type of toxicity is also known as "oxidative stress", and is seen in the early stages of Alzheimer's disease.
Several studies have shown different metal concentrations (Cu, Zn and Fe) between healthy and diseased patients.
Beyond the concentrations at the global level of the brain, what matters is the distribution of metals between extra and intracellular environment.
Although the cerebral levels for these three metals are impacted, copper was chosen as the preferred therapeutic target because, being found mainly in the form of nanoparticles, it can participate in oxidative stress unlike the other two.
To date, two clinical trials have been conducted to restore the homeostasis of metals (their good internal balance), but they had to be stopped due to a lack of specificity and purity of the molecules tested for their transport.
To overcome these problems, we have designed a new molecule capable of specifically transporting copper.
Not only does it bond very preferentially with this metal, but it is also able to extract it from Aβ.
It also stops the production of reactive oxygen species, and brings copper back inside neuronal cells where it is normally used by various proteins and enzymes for their proper physiological functioning.
This molecule, capable of moving copper from the outside where it is harmful to the inside of the cell where it is needed, therefore represents a valuable new tool in fundamental research.
It will allow a better understanding of the implications of a deregulation of the quantities of copper in Alzheimer's disease and, moreover, presents potential therapeutic applications by repositioning it correctly.
Before considering its therapeutic use, we are continuing our work on more integrated models such as three-dimensional hippocampal sections of mouse brains.
These models make it possible to better study the impact of neuronal degeneration in a model that has preserved the spatial organization of this major brain area.
Hopes for tomorrow
In conclusion, for a multifactorial disease such as Alzheimer's disease, it is necessary to focus on several therapeutic targets proteins Aβ, Tau, metals... And this, as early as possible in the establishment of the disease in order to achieve an improvement in clinical manifestations.
OUR "ALZHEIMER'S DISEASE" FILE
In this context, we have developed a new molecule capable of transferring excess extracellular copper to the inside of the cell that lacks it.
This targets several factors: the aggregation of Aβ modulated by metals, the production of reactive oxygen species by copper bound to toxic Aβ for neurons, and the lack of intracellular copper which affects proper cellular functioning.
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