The Australian Mutation

Biophysicists have found out how the "Australian mutation" leads to Alzheimer's disease

MIPT Press Service

Scientists from MIPT and IBH RAS, using the example of one hereditary genetic mutation, have revealed common initial molecular mechanisms that can lead to both premature forms of Alzheimer's disease and age-related changes in the human body. Knowledge of these mechanisms is necessary to find new targeted ways to treat this neurodegenerative disease, which is increasingly covering the "aging" developed countries of the world. The results of the work are published in the journal ACS Chemical Biology.

Dementia is a syndrome in which there is a degradation of memory, thinking, behavior and the ability to perform daily actions. Alzheimer's disease is the most common cause of dementia, accounting for 60-70% of all cases (according to a WHO report). This puts it in a number of socially significant diseases, for the fight against which huge funds are allocated - both budget and pharmaceutical companies. Such famous politicians as Margaret Thatcher and Ronald Reagan suffered from Alzheimer's disease at the age. As a rule, the disease is detected in people over 65 years old, but sometimes it is diagnosed in people 40 years old or even earlier. Approximately 10-15% of cases of premature Alzheimer's disease are the result of a hereditary genetic predisposition, which eventually leads to premature pathology. At the same time, comprehensive studies of hereditary, so-called "family" mutations can suggest key mechanisms for the development of Alzheimer's disease, especially its initiation. 

Alzheimer's disease is accompanied by the accumulation of amyloid plaques in the brain tissues, which are formed from pathogenic forms of β-amyloid peptides. These peptides are short (about 40 links in the amino acid sequence) fragments of the protein ARP (amyloid precursor protein), penetrating through the membrane of brain cells. During the vital activity of neurons, the breakdown of the ARP protein occurs by various enzymes. If the "large" protein ARP (the biological function of which is still not fully understood) is sequentially "cut" by the enzymes β- and γ-secretase, then β-amyloid peptides are formed, which in small quantities are necessary, apparently, to maintain brain function. However, the γ-secretase sequentially cuts the APP protein chain (inside the neuronal membrane) into fragments with slightly different lengths.This is how relatively "non-pathogenic" and "pathogenic" forms of β-amyloid peptides arise. The main pathogenic form consists of 42 amino acid residues (Aß42), while the less pathogenic form consists of 40 (Aß40). In healthy people, the ratio of Aß42/Aß40 is small, about 1/9. A larger numerical ratio of Aß42/Aß40 indicates excessive production of Aß42, which leads to pathology. To date, scientists are testing the hypothesis that beta-amyloid peptides are active molecules of the innate immunity of the human nervous system, and their intensive release is associated with various inflammatory processes and damage to brain tissues. At the same time, most familial mutations in the sequence of the ARP protein, which are associated with the premature development of Alzheimer's disease, are found in the membrane region of this protein. 

The aim of this work was to study the hereditary "Australian" mutation (L723P) in the membrane segment of the ARP protein, which is associated with the early development of Alzheimer's disease. The scientists investigated the structural and dynamic behavior of the mutant form of the membrane fragment of the ARP protein, comparing it with the non-mutant form using protein engineering techniques, high-resolution nuclear magnetic resonance (NMR) spectroscopy and computer modeling. Using NMR spectroscopy, the mutant form of the ARP peptide was studied in comparison with the non-mutant one according to such parameters as the distribution of the "helicity" of the amino acid chain, its stability and flexibility, as well as the availability of the chain for lipids and water molecules. The researchers found that the L723P mutation locally unfolds the terminal spiral of the membrane segment of the ARP protein, and also straightens and stabilizes the segment itself in the center of the lipid membrane. In addition, it was noticed that the mutation increases the availability of this segment for water molecules, which shifts the "frame" of its cleavage by enzymes. Thus, there is a switch between pathogenic and non-pathogenic cascades of splitting the ARP protein: the ratio Aß42/Aß40 increases, and the total concentration of β-amyloid in brain tissues increases.

Illustration of the molecular basis of the pathogenesis of hereditary and age-related forms of Alzheimer's disease. Source: Eduard V. Bocharov et al.; ACS Chemical Biology.

Eduard Bocharov, Senior Researcher at the Laboratory of Biomolecular NMR Spectroscopy of the IBH RAS and the Laboratory of Aging and Age-related Neurodegenerative Diseases of MIPT, explains: "Of course, this work affects only part of the causes of multi-sided Alzheimer's disease, the molecular mechanisms of pathogenesis of which are being studied in many laboratories around the world. In particular, the main "player" – the membrane protein ARP – and its sequential cleavage by secretases in the membrane of neurons are intensively studied. We have described a cascade of events occurring inside and near the cell membrane at the time of cutting of the ARP protein by the enzymatic γ-secretase complex. Thus, using the example of one "Australian" mutation, the molecular basis of pathogenesis has been revealed, which can lead to both premature development of Alzheimer's and forms of the disease associated with age-related changes in the human body."

The results of the study reveal a simple molecular mechanism of the development of Alzheimer's disease, directly related to the influence of the "Australian" mutation on the structural and dynamic properties of the membrane segment of the ARP protein. This leads to the harmful cleavage of the ARP protein by secretase enzymes and the intensive accumulation of pathogenic forms of β-amyloid around neurons. It is noteworthy that the age-related development of Alzheimer's disease can be explained by similar mechanisms, where instead of mutation, for example, oxidative stress or a certain lipid composition of neuronal membranes, including excess cholesterol, will act. A detailed understanding of the molecular mechanisms regulating the formation of amyloidogenic peptides is necessary to create new targeted treatments that directly affect the primary link of the pathogenetic process of Alzheimer's disease.

Portal "Eternal youth" http://vechnayamolodost.ru