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Pathophysiology aspects related to the involvement of the tau protein and beta-amyloid in Alzheimer's disease.

INTRODUCTION

Alzheimer's dementia is a neurodegenerative disease characterized by progressive cognitive decline (1). This irreversible process leads to the slow destruction of one's cognitive functions and memory, and to the loss of one's intellectual capacity and personality, which influence one's daily life (2, 3). This type of dementia is one of the most common in the adult population, affecting about 27 million people worldwide in 2010. This number is expected to significantly increase up to 100 million people by 2050 (4). This condition has become a real problem among the elderly worldwide and it has turned into a real challenge in both developed and developing countries (5, 3). It is important that patients be diagnosed in the early stages of the disease, and the diagnosis should be set based on clinical symptoms and on specific psychological tests (6). Early diagnosis supports the future course of care and the improvement of the quality of life of that person (7).

The findings of several epidemiological studies revealed a considerable increase of the tau protein and a decrease of the beta-amyloid level in the cerebrospinal fluid (6, 8). One of the assumptions on which relies Alzheimer's disease triggering would be the decrease of the amount of beta-amyloid present in the brain and its accumulation in the central nervous system. Beta-amyloid is carried by albumin into the blood stream, its decrease will lead to a decrease in the albumin--beta-amyloid complex levels, and then to the onset of the disease due to beta-amyloid accumulation at the central level (6, 9).

According to another assumption, the tau proteins are suspected to accumulate in the cells and lead to the formation of the so-called pathological neurofibrillary tangles. Tau proteins make up the microtubules, one of the neuronal cytoskeleton components playing an important role in neuron morphology and structure. Kinase and phosphatase action support the proper functioning of these proteins. An abnormal hyperphosphorylation process, accompanied by microtubule disorganization and tau protein accumulation is specific to Alzheimer's disease (10, 11).

ALZHEIMER'S DISEASE AND NEURODEGENERATION

An increase in the number of old individuals (over 65 years of age) suffering from neurodegenerative disorders has been noted in industrialized countries as early as the past century (12). Both neurodegenerative diseases and Alzheimer's disease may be diagnosed by clinical symptoms, medical imaging scanning and biomarkers, such us the accumulation of beta-amyloid plaques in the brain or of tau proteins (12).

The ageing process leads to the development of amyloid plaques even in the absence of Alzheimer's disease. They are made up of beta-amyloid, which accumulates due to the distorted cleavage of the transmembrane protein (12). This protein normally plays an important role in signal transmission, axon elongation and at cellular level, as well as in gene expression by means of the C-terminal domain (13). When the amyloid plaques are cleaved, aberrantly the first signs of Alzheimer's dementia occur, due to a beta-amyloid overproduction accumulating in the brain (13).

The monomer form of beta-amyloid is apparently non-pathogenic, whereas the oligomer form is sinaptotoxic, leads to hippocampus and parahippocampal gyrus impairment, with a clinical response consisting of progressive memory degradation. A high affinity oligomer may induce axonal degeneration, neuronal synapse loss, neuronal loss by Fyn kinase activation (14).

MICROGLIA, NEUROINFLAMMATION AND BETA-AMYLOID IN ALZHEIMER'S DEMENTIA

Several causes leading to beta-amyloid generation and accumulation in connection with Alzheimer's disease have been studied over time, namely free radical production, mitochondrial dysfunction, genetic factors, cardio-cerebral factors, metabolic factors, brain injuries and last, but not least, inflammatory processes. All these lead to beta-amyloid production in pathological amounts with the occurrence of a neuronal dysfunction and subsequently to cell death (3, 15, 16).

Microglia is represented by a population of phagocytes, which migrate in the central nervous system and settle between the white and grey substance. It may be located next to the beta-amyloid plaques in Alzheimer's disease patients, playing a double role by removing the beta-amyloid by means of phagocytosis or may facilitate beta-amyloid deposit by neurotoxic proteases and by means of inflammatory factors (17).

Neuroinflammation is a complex process by which the brain responds by means of lymphocytes, monocytes, and macrophages to infections, diseases, and lesions, being a potential therapeutic target in Alzheimer's dementia prevention (3). The most recent clinical trials have revealed that microglia activation inhibition may support the treatment of the disease when a possible neuroinflammation theory is involved (3).

Just like the other macrophages in the body, microglial cells act by a cytotoxic and phagocytosis mechanism on foreign bodies; they also play an antigen role by maintaining homeostasis by cytokine secretion (3). There are studies proving that microglial activation relies on neurotoxic and proinflammatory factors, which includes cytokines like TNF-alpha, IL-1beta, free radicals, fatty acids (3).

There are two types of neuroinflammation: acute and chronic. In the acute form, microglial cells are activated and inflammatory mediators, cytokines and chemokines, with reparatory effect on the impaired body, are released (3). Chronic neuroinflammation acts by releasing inflammatory mediators successively after the initial lesion, being harmful to the nervous tissue; this chronic inflammatory process leads to neuron degeneration (3).

Microglia activation in the brain and spinal cord in Alzheimer's disease plays an important role by progressively leading to homeostasis loss, neuronal lesions and even cell death due to the cytotoxic factors released, including cytokines, chemokines (3). There are two types of cytokines with a role in Alzheimer's dementia: the proinflammatory and the anti-inflammatory ones. The former exacerbate the inflammatory reactions, whereas the latter limit inflammation. Pro-inflammatory cytokines appear through glial cell activation and play an important role in depression onset and neurodegenerative lesions in the elderly; these impairments are also specific to Alzheimer's disease (3, 18).

The production and decrease of the amount of beta-amyloid plays an important role in the progress of Alzheimer's disease. Although microglial cell activation may lead to an increase in the amount of beta-amyloid and to the slowing down of the progress of the disease, microglia accumulation leads to the release of inflammatory mediators and to the decrease of the amount of beta-amyloid, hence to the loss of functional integrity (19). Beta-amyloid production and accumulation by plaque formation play an essential role in oxidative stress, inflammation, apoptosis and, most importantly, activate microglial cells thus triggering Alzheimer's disease activation (3).

The mechanism and means by which beta-amyloid induces neuroinflammation by glial cell activation has been proven by in vivo and in vitro studies (20). Oxidative stress induced by beta-amyloid may be, both, a cause and a consequence of neuroinflammation that influences disease pathogenesis. Glial cell activation by betaamyloid leads to cytokine and chemokine production and to neuronal damage due to glial maturation (3). There are studies that prove that, from a pharmacological point of view, by preventing beta-amyloid from inducing microglial activation a drop in cytokine production is achieved, and the beta-amyloid deposits are reduced, thus remitting the clinical symptoms (21). Inflammation inhibiting drugs, such as ibuprofen and indometacin, may protect people with a predisposition to Alzheimer's disease, by causing a drastic decrease of beta-amyloid levels in the brain (21).

MORPHOFUNCTIONAL INVOLVEMENT OF THE TAU PROTEIN IN ALZHEIMER'S DISEASE

The human tau gene is located on the long arm of the 17 chromosome and includes 16 exons. In the central nervous system, only exons 2, 3 and 10 are able to express themselves alternatively during brain development (22). Tau protein was discovered by accident when the factors leading to microtubule formation were analyzed in 1970 (11).

Tau protein belongs to a group of proteins called MAP--proteins associated to microtubules, which have certain characteristics like heat resistance and which do not lose their function being in contact with an acid. (10). Biophysical studies have proven that this protein is a true prototype, its structure being visible only by nuclear magnetic resonance spectroscopy, a method which allowing the description of its conformation (10). There are six tau protein isoforms, which may contain three or four domains of tubulin binding to 31 or 32 amino acids in the C-terminal section and one or two insertions for another 29 amino acids in the N-terminal section (10).

The sizes of these isoforms vary and depend on the presence or absence of exons 2, 3, or 10. The sequences encoded by exons 2 and 3 play a role in tau protein acidity, whereas exon 10 may encode a positively charged sequence. (10)

The N-terminal area has a 3.8 isoelectric point and the C-terminal area is positively charged with a 10.8 isoelectric point. Actually, tau protein is a true dipole with opposite charges, its isoforms playing an important role in the brain development stages; this protein is present both in the axons and in the oligodendrocytes (10). The N-terminal area of the tau protein is a projection domain, which may determine the distance between microtubules in the axon and leads to axon diameter increase. (10)

Tau protein also interacts with other components of the membrane cytoskeleton, by spectrin and actin binding. Another molecule with which it interacts is peptidylprolyl cis/trans isomerase Pin 1, a protein that helps tau protein function regulation, with an important role in degeneration protection during the ageing process. (10) Pin 1 protein activation is poor in Alzheimer's disease. Tau protein also binds through its proline section to Fyn kinase of the Src family; this association depends on the tau protein phosphorylation process. Pathological tau protein may bind to Fyn kinase in the postsynaptic compartment, thus leading to toxicity increase (10). The Fyn kinase and tau hyperphosphorylation interaction cause an axonal demyelinating process, which impairs microtubule stability and alters neuroplasticity (10).

In Alzheimer's disease, tau protein loses its ability to bind to the microtubules due to the conformation changes, which lead to aberrant aggregation in the neuron. This structural alteration mainly affects the microtubules, but also other processes in which tau protein is involved (10). There are several hypotheses related to the mechanism by which tau protein becomes non-functional, the main cause being an abnormal translation change. Here are other causes due to which tau protein becomes pathological: hyperphosphorylation, acetylation, glycation, and proteolytic cleavage (10).

Through phosphorylation, tau protein may bind to the microtubules, thus supporting their proper functioning, yet hyperphosphorylation results in the loss of this feature. When in a normal mature neuron tubulin is surrounded by tau proteins, in neurons affected by Alzheimer's disease this connection is virtually absent, tau protein even leading to microtubule assembly and organization disorders. (23) There are studies that prove that abnormal tau protein breaks the bound between normal tau proteins and microtubules in the cytosolic phase. One may notice that, in the in vitro model analyzing ethanol-induced neuronal apoptosis, tau protein hyperphosphorylation occurs before its cleavage (10). Hyperphosphorylation is an important aspect that tau protein accumulation in the brain of Alzheimer's disease patients relies on (10).

A series of studies revealed that tau protein acetylation as a post-translational change may regulate tau protein function. Tau molecule has negatively and positively charged areas and cannot be associated with hydrophobic molecules. In vitro studies on tau protein aggregation have proven that tau protein auto-aggregation is prevented by the terminal sections composing it, i.e. C-terminal and N-terminal. A large amount of tau protein would be required to be able to polymerize or other cofactors would be necessary to help the protein auto-assembly process (10, 24).

The proteolytic cleavage of tau protein is another mechanism playing a role in abnormal tau protein aggregation. This aberrant proteolysis in the brain of Alzheimer's disease patients leads to apoptosis. Studies on transgenic cell and animal cultures analyzed what would happen if they were to cleave only the C-terminal ending in the tau protein structure and the findings revealed the subsequent normal functioning of the cells (10). Tau protein also contains caspase cleavage sites, an enzyme with proteolytic role that leads to cell death, playing a vital role in neuronal death induction (25). The proteolysis process and abnormal role of tau protein cleavage were later proven by clinical-pathological studies in dementia development evolution. The findings of the specialized studies reveal the fact that proteolytic cleavage is a pathological process and a marker in Alzheimer's disease diagnosis (10).

TAU PROTEIN IN NEURODEGENERATIVE CONDITIONS

The brains of Alzheimer's disease patients contain beta-amyloid deposits at extraneuronal level and tau protein accumulations at intraneuronal level. There are mutations in the beta-amyloid precursor protein gene, which leads to early disease onset; these mutations affect the beta-amyloid aggregation and type. The same thing occurs in the case of type 1 (presenile) or type 2 (presenile mutations), the genetic intervention mechanism alone being responsible for the occurrence of the disease. It seems that tau protein is involved in several degenerative diseases, and beta amyloid triggers pathological tau protein (26, 27).

Studies conducted on transgenic mice and on cell cultures have showed the ability of beta-amyloid to pathologically affect tau protein. A post mortem study conducted on human subjects known to have suffered from Alzheimer's dementia revealed the isolation of dimeric beta-amyloid forms in their brains. At a later stage, these forms of beta-amyloid were brought into contact with the hippocampus tissue of a rat and they noted a tau protein hyperphosphorylation process and tau protein accumulation in the hippocampic area of the brain of the rat, as well as the occurrence of neurodegeneration. It seems that one of the possible connections by which betaamyloid causes tau protein changes would be Fyn tyrosine kinase, a hyperphosphorylation trigger (26, 28).

The loss of the tau protein function and its turning into a pathogenic protein is a much discussed topic. Both tau protein hyperphosphorylation and aggregation impair microtubule formation, and alter neuronal dynamics and stability. Microtubules play an important role in axons, and synapses and molecular transport are disrupted; hyperphosphorylation increases toxicity and later leads to apoptosis (26).

Both beta-amyloid plaques and tau protein filaments are microscopic deposits involved in Alzheimer's disease pathogenesis. Tau filament formation is more influenced by the neurodegenerative process than beta-amyloid plaques, as its oligomeric forms are deeper involved in disease pathogenesis. (26)

ANTIBODIES--A FUTURE STRATEGY IN ALZHEIMER'S DISEASE PREVENTION AND THERAPY

Tau immunization may be another future therapeutic and preventive approach to Alzheimer's disease. Despite the common belief that antibodies are unable to cross the hemato-encephalic barrier, some stud ies have shown that the small amounts of anti-beta amyloid antibodies may penetrate the brain. Although beta-amyloid is located in extracellular areas, whereas tau protein occurs at the intracellular level, anti-tau antibodies may cross the endocytosis and reach the cell to interact with the synapses before tau protein aggregation and hyperphosphorylation (29).

CONCLUSIONS

Alzheimer's disease is a condition specific to the elderly, a progressive neurodegenerative disease, which is one of the most common types of dementia.

There are several factors contributing to the formation of beta-amyloid deposits and to the formation of beta-amyloid plaques, such as oxidative stress, genetic factors, homeostasis loss, environmental factors and last, but not least neuroinflammation. Betaamyloid is responsible for pathological tau protein emergence by means of Fyn kinase.

Tau protein is part of the microtubule structure and plays an important role in proper neuronal functioning. Due to the hyperphosphorylation, acetylation glycation and proteolytic cleavage processes, tau protein becomes pathological and leads to neuronal apoptosis.

Knowing the morphofunctional aspects of tau protein and beta-amyloid, as well as the mechanism of their involvement in Alzheimer's disease, is useful for early diagnosis setting and in the strategies concerning the prevention and therapy of this neurodegenerative disease.

ACKNOWLEDGMENTS AND DISCLOSURE

The authors declare have no potential conflicts of interest to disclose.

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Georgiana DRAGAN--Resident in neurology, Ph. D. Student, Department of Pathophysiology, Faculty of Medicine, "Gr. T. Popa" University of Medicine and Pharmacy Iasi, Romania

Romeo DOBRIN--M. D., Ph. D., Lecturer, Senior Psychiatrist, "Gr. T. Popa" University of Medicine and Pharmacy Iasi, Romania

Manuela CIOCOIU--M. D., Ph. D., Professor, Department of Pathophysiology, "Gr. T. Popa" University of Medicine and Pharmacy Iasi, Romania

Correspondence:

Romeo DOBRIN

M. D., Ph. D., Senior Psychiatrist, lecturer, "Socola" Institute of Psychiatry Iasi, "Gr. T. Popa" University of Medicine and Pharmacy No. 16, Universitatii Street, zip code 700115, Iasi, Romania

E-mail: romeodobrin2002 @gmail.com

Submission: March, 29th, 2017

Acceptance: May, 05th, 2017
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Author:Dragan, Georgiana; Dobrin, Romeo; Ciocoiu, Manuela
Publication:Bulletin of Integrative Psychiatry
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Date:Jun 1, 2017
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