With respect to Alzheimer’s disease, Jean-Marc Sabatier was the first to establish a direct link between Parkinson’s disease and a dysfunctional renin-angiotensin system. explanation.
Neurodegenerative disease of Parkinson’s disease
Parkinson’s disease affects more than 9 million people worldwide, including more than 200,000 in France (incidence of 3.2 men per 1,000 and 2 women per 1,000). In France, he is the second most common neurodegenerative disease. Alzheimer’s diseaseThe disease is chronic, progresses slowly over years, is rarely observed before age 45, and prevalence is between ages 85 and 89 (genetic origin is seen in 5% of cases). increase). It is characterized by resting tremor (dopamine deficiency triggers depolarization of striatal acetylcholine neurons), slow movement (bradykinesia), limb stiffness (hypertonus), or stiffness of movement (due to worsening muscle tone). ) is a neurodegenerative pathology associated with motor symptoms such as muscles that cause spasms and pain in various muscles or tendons), and postural imbalances.
400,000 neurons in the substantia nigra
The disease is also characterized by psychiatric, cognitive, sensory (including pain), and sleep disturbances. During Parkinson’s disease, the destruction of a specific population of neurons is observed: dopamine neurons called dopaminergic neurons. These neurons are involved in controlling movement and are found in the substantia nigra (or substantia nigra) of the brain. The substantia nigra (subdivided into the compact and reticular areas) is a small neural structure composed of about 400,000 dopaminergic neurons (these neurons are pigmented because they contain neuromelanin), and their cells The body transmits expansion to the striatum. cerebral nuclei.
Dopamine is a neurotransmitter present in large amounts at the presynaptic terminals of these neurons, hence the name dopaminergic neurons. They can release dopamine in striatal structures called the caudate nucleus and putamen.
Substantia nigra lesions
Thus, the substantia nigra and striatum are highly dopamine-rich brain structures (the reticular region of the substantia nigra locus is composed of GABAergic neurons). In patients with Parkinson’s disease (Parkinson’s disease), lesions in the substantia nigra of the brain are observed, corresponding to the progressive loss of dopaminergic neurons. This depletes dopamine in this area of the brain. In more advanced stages, dopamine deficiency results in an inability to activate the striatum and a significant reduction in dopamine content. Because the number of dopaminergic neurons decreases, the substantia nigra becomes pale.
Within the remaining dopaminergic neurons, inclusion bodies (Lewy bodies), characteristic of Parkinson’s disease, appear. Lewy bodies are “mysterious” aggregates of proteins within nerve cells, composed primarily of neurofilaments (the main structural protein of neurons) and primarily α-synuclein (a protein involved in the formation of synapses) . In Parkinson’s disease, death of neurons, especially dopaminergic neurons in the early stages of the disease, is associated with the formation of these protein aggregates and inflammation of brain tissue involving microglial cells (innate immunity) and T lymphocytes. It seems that (adaptive/acquired immunity). In Parkinson’s disease patients, the native α-synuclein protein changes its three-dimensional structure, acquiring an ‘abnormal’ spatial shape that favors the formation of protein aggregates. Furthermore, ‘aberrant’ α-synuclein can convert ‘normal’ α-synuclein into an ‘aberrant’ form. This change in the three-dimensional structure of α-synuclein spreads within the same dopaminergic neurons and is transmitted from neuron to neuron in the nigrostriatal region of the brain responsible for motor coordination.
Certain metals and pesticides promote disease
Parkinson’s disease damage (synucleinopathy = presence of Lewy bodies) is not limited to dopaminergic neurons in the substantia nigra. It can be observed in the cerebral dopaminergic neurons of the olfactory bulb, the corticolimbic pathway, and the enteric nervous system (gut neurons). In advanced disease, other neuronal populations associated with neurotransmitters other than dopamine (serotonin, norepinephrine, acetylcholine, etc.) are affected by neurodegeneration and synucleinopathy. In Parkinson’s, people remain asymptomatic until 50-70% of dopamine neurons are destroyed (brain plasticity compensates for this neuron loss).
While it is worth noting that exposure to certain metals and pesticides facilitates the development of Parkinson’s disease, coffee and tobacco consumption appear to be preventive. have a 30% higher risk of dying from Covid-19, including pneumonia.
Renin-angiotensin system (RAS) and its dysregulation (e.g. SARS-CoV-2 and vaccine spike protein)
The SARS-CoV-2 virus causes hyperactivation/dysregulation of the renin-angiotensin system or RAS (also known as the angiotensin-aldosterone system or AAS), a physiological system central to human function. . RAS is responsible for renal, pulmonary, and cardiovascular autonomic (automatic) functions. It also regulates innate immunity and the body’s various microbiota. RAS is ubiquitous in the human body as it is present in cells of various tissues and organs. Dysfunctional RAS (because it is over-activated) contributes to Covid-19 pathology via excess of the angiotensin-2 hormone, which releases aldosterone and over-activates the ‘harmful’ receptor AT1R. directly involved. Indeed, overactivated AT1R receptors by excess angiotensin-2 have a number of harmful activities in the human body through triggering cell signaling cascades. Overactivated RAS and AT1R receptors are pro-hypertensive (vasoconstriction of blood vessels), pro-inflammatory (pro-inflammatory cytokine storm), pro-oxidative (generation of harmful reactive oxygen particles), and pro-thrombotic (occlusion). thrombus formation). blood vessels), pro-angiogenesis (blood vessel and tumor growth), pro-hypoxemia (reduced oxygen load of red blood cells), pro-hypoxia (impaired oxygen supply to cells, tissues and organs), pro-fibrosis (organ fibrosis) disease), hypertrophy (enlargement of the heart and blood vessels), and depletion of nitric oxide (inflammation, impairment of immune and memory processes).
RAS hyperactivation and Parkinson’s disease
Parkinson’s disease has been observed in some people after natural infection with SARS-CoV-2 and/or Covid-19 vaccination. for example, Dr. Pardis Zarifkar (Copenhagen National Hospital, Denmark) reported a 2.6-fold increased risk of developing Parkinson’s disease in the Danish population following SARS-CoV-2 infection (for Alzheimer’s the risk appeared to be 3.5-fold higher). is).
Australian researchers (University of Queensland, Australia) have shown that SARS-CoV-2 can cause brain inflammation. Her RAS involvement in neurological disease has been demonstrated. RAS components are produced and activated intracellularly (endocrine RAS activity), especially in the central nervous system. As mentioned above, viral infection with SARS-CoV-2 (or anti-Covid-19 vaccination) causes RAS dysfunction via excess angiotensin-2, which induces aldosterone secretion by the adrenal glands, resulting in a causative “harmful ”causes hyperactivation of the AT1R receptor. Covid-19 disease.
Overactivation of RAS is associated with hypertension, a major contributor to neurodegenerative diseases and brain dysfunction. RAS inhibitors (eg, sartans, ACE inhibitors of angiotensin-1 converting enzyme) have been shown to have beneficial effects in neurodegenerative diseases and cognitive impairment. Thus, excess angiotensin-2 hormone is associated with neuropathy. Nervous system cells (neurons, oligodendrocytes, astrocytes, microglial cells) have ACE2 (angiotensin-2 converting enzyme) receptors on their surface that are targets of the SARS-CoV-2 spike protein (or vaccine spike protein) . Binding of the spike protein to the ACE2 receptor induces excess angiotensin-2 and hyperactivation of the pro-inflammatory AT1R receptor. The latter are activated M1 microglial cells (innate immunity) and T cells (adaptive/acquired immunity).
The AT1R receptor is also a pro-oxidant, stimulating a redox enzyme (NADPH oxidase Nox) responsible for increasing the number of reactive oxygen particles within mitochondria (energy centers of cells), leading to mitochondrial dysfunction and programmed neuronal death. or induce cell death (via apoptosis). ). Similar to the formation of intracellular aggregates of tau protein or extracellular amyloid beta protein in Alzheimer’s disease, the accumulation of intracellular protein clusters of neurofilaments and α-synuclein (Lewy bodies) in Parkinson’s disease is associated with hyperactivation of RAS. must be due to It is noteworthy that the hypertensive-promoting effects of overactivated RAS contribute to the restriction of blood flow in the brain, promoting neurovascular uncoupling, brain hypometabolism, and development of neurological damage. To do.
How to counter the disability associated with Parkinson’s disease and caused by RAS dysfunction?
Drugs used in Parkinson’s disease are generally dopamine and molecules that enable dopamine synthesis (L-dopa is a neurotransmitter precursor). A strategy of infrared extracranial illumination is being tested in Grenoble to reactivate dopamine secretion! Extends the life of dopamine by blocking transferase enzymes (such as the MAO-B enzyme selegiline). Supplementation with tyrosine and phenylalanine (two aromatic amino acids) aids in dopamine synthesis as well as micronutrients (copper magnesium, zinc, manganese, vitamins PP, B6, B9, etc.). Various inhibitors of RAS, such as vitamin D, are important, and vitamin D has been shown to act as a negative regulator of RAS (by inhibiting renin production) and reduce cognitive impairment, neurodegenerative disease, and cerebrovascular disease. has a protective effect against At the level of RAS, angiotensin-2 can bind with very different affinities to the AT1R and AT2R receptors. These RAS receptors are expressed in brain regions associated with autonomic, cognitive, and motor control functions. AT1R and AT2R receptors are responsible for most of the dopamine in the parietal pars compacta of the sunspot (the “black part” consisting of dopaminergic neurons afferent to other brain structures: the caudate nucleus and the putamen belonging to the striatum). ). manufacturing. In addition, various elements of RAS have been identified in dopaminergic neurons, which are favored cellular targets in early Parkinson’s disease.
With respect to Alzheimer’s disease, there is a direct link between a dysfunctional renin-angiotensin system (due to overactivation by viral or vaccine spike proteins) and the neurodegenerative disease of Parkinson’s disease. Apparently, other neurodegenerative diseases, whether dependent on host infection with SARS-CoV-2 or not, are also associated with her RAS dysregulation. This is illustrated by the apparently beneficial and protective effects of her RAS inhibitors on the incidence and severity of neurological pathologies in humans.
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