2023-12-04 23:00:00
A new cellular mechanism, recently discovered, might largely explain the degeneration observed in Alzheimer’s, but also concern other pathologies associated with aging.
Alzheimer’s disease still has no certain explanation. Science only notes that two types of lesions characterize the “acute” phase of the disease: amyloid deposits (due to proteins of the same name) and neurofibrillary tangles (caused by hyperphosphorylation of Tau proteins). However, these two phenomena do not are perhaps not the “original” causeIndeed, the various clinical trials which, for several years, have targeted these proteins have not had the expected results.
Alzheimer’s would begin well before the first obvious symptoms
Faced with the impasse of these weak results, some research is taking other directions. THE chronic stress is one of the avenues currently being studied: it might constitute the true source of this degenerative disease, asaccelerator of aging.
It now appears certain that the first symptoms of Alzheimer’s result from a long prior silent evolution ; a “continuum” which manifests itself, in the early stages, as mild cognitive impairment, but not sufficiently pronounced or obvious to significantly affect daily activities. Affected people can thus very well occasionally complain regarding subtle deficiencies and display normal performance in standard tests.
The whole difficulty lies in this early detection, knowing that the chances of slowing the progression of the disease are greatest when we intervene at the earliest stages . The usual brain imaging (PET scan and MRI) and invasive lumbar punctures will probably be replaced, in the near future, by new blood, saliva, urine, retinal markers or even the new “light” imaging technique called ” magnetoencephalography » – using a cap riddled with sensors to be placed on the skull – which should allow a diagnosis more upstream than current examinations.
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Chronic stress, powerful enough to initiate Alzheimer’s?
Several studies (1) looked at the responsibility of chronic stress in the onset of Alzheimer’s disease. It is established that stress affects multiple neural pathways and brain systems , notably activating the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis. This results in a significant production of cortisol ; but this hormone is able to cross the blood-brain barrier to bind to neuronal receptors located on the hippocampus, amygdala and prefrontal cortex. Furthermore, the body’s response to chronic stress also involves the immune system, through production of pro-inflammatory cytokines capable of directly influencing neuronal activity in the brain.
These imbalances, when they persist, lead to a accelerated aging . They also have an even greater impact with age, with the capacity to resist chronic stress and its consequences decreasing significantly among seniors. A study (2) Swedish study reveals that people aged 18 to 65 subject to the chronic stress or to the depression have a risk twice as high to contract Alzheimer’s, and that this risk is even four times higher when both conditions are met.
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The ATM protein, perhaps the key in the degenerative process
Faced with the lack of success of treatments targeting amyloid plaques and the accumulation of Tau protein, an Inserm research team decided to investigate (3) further upstream, the so-called “oxidative” stress which, when it is no longer properly controlled by the body, leads to accelerated aging. Alzheimer’s disease is then considered as one symptomatology among others of global aging of the person.
The team thus realized that another protein seemed decisive: called “ ATM » (ataxia telangiectasia mutated)this molecule is involved in the detection and repair of DNA double-strand breaks and in the cell cycle control. It seems to be a major player in the response to all forms of oxidative stress.
This type of stress is characterized by the massive formation of the famous free radicals (now called “oxygenated radical species” or “reactive oxygen species”, or ROS), chemically very reactive, to the point of being able to damage (literally “break”) DNA.
The researchers noticed that has following oxidative stress due for example to irradiation or exposure to heavy metals or pesticides, many copies of the ATM protein are produced in the cytoplasm of the cell then directed towards the nucleus to detect and repair DNA breaks.
The trouble is that ATM migration can be hindered when the protein meets and binds to other proteins during this process. These “new” proteins, called “X”, can be very diverse in nature depending on the individual and depending on the tissue we are considering and the disorders to which it is subjected. According to the authors, it is possibly these X proteins, through their mutations, which are at the origin of diseases.
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An accumulation of DNA breaks leading to degeneration and then cell death
In the case of Alzheimer’s, the most credible proteinapolipoprotein Eor APOE, due to the strong polymorphism attributed to it in a large majority of patients and its sites of preferential interaction with ATM.
By studying ten lines of skin cells from Alzheimer’s patients at different stages of the disease, the Inserm team found that all systematically presented a overexpression of APOE protein around the nucleus .
The scenario envisaged would therefore be the following: oxidative stress – whatever its origin, endogenous or exogenous – leads to APOE overexpression which promotes “ capture » and agglutination with ATM around the nucleus, while the DNA breaks due to stress are increasing without being able to be repaired (due to immobilization of the ATM), until degeneration, then death of the cell.
Hence the idea that any carrier of cells overexpressing the APOE protein around the nucleus might be predisposed to Alzheimer’s disease – and the temptation to derive an early diagnostic tool from it, as is being studied at Neolys Diagnostics, in Bas-Rhin.
A molecular approach also valid for other degenerative diseases?
The Inserm team has also observed this process in other diseases such as retinoblastoma, Duchenne muscular dystrophy, Huntington’s disease, tuberous sclerosis of Bourneville or even Usher syndrome, with each time another specific protein in the role of protein X neutralizing ATM. This capture of the ATM protein might therefore constitute an important key in the triggering and evolution of premature aging and many diseases. As well as in the initiation of new therapeutic avenues.
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