INTRODUCTION:

Tau proteins are the stabilized form of microtubule associated protein (MAP) of a normal motor neuron.The other two neuronal MAPs are MAP1 and MAP2.Tau proteins are found abundant in nerve cells of the cardinal neural system.They are the product of alternative splicing of the single gene located in the chromosome 17.⁽¹⁾Tauopathies are a heterogeneous group of neurodegenerative diseases characterised by abnormal metabolism of tau proteins leading to intracellular accumulation and formation of neurofibrillary tangles (NFT). These neurofibrillary tangles are deposited in the cytosol of neurons and glial cells.

STRUCTURE AND FUNCTION OF TAU PROTEINS:

Six isoforms (2) of tau protein differ according to the contents of three (3R) or four (4R) tubulin binding domains (repeats, R) of 31 or 32 amino acids in the C-terminal region of tau protein and one (1N), two (2N), or no inserts of 29 amino acids each in the N-end part of the atom.These isoforms, which diverge in size from 352 to 441 amino acid residues, are linked to the presence or absence of sequences encoded by exons 2, 3, or 10. Inclusion of the imperfect repeat region encoding exon 10 leads to the expression of tau containing four microtubule-binding repeats (MTBRs) (4R tau: 0N4R, 1N4R, 2N4R), while the exclusion of exon 10 results in splicing products expressing tau with three MTBRs (3R tau: 0N3R, 1N3R, 2N3R) ⁽³⁾. These six isoforms are also mentioned to as τ3L, τ3S, τ3, τ4L, τ4S, and τ4.⁽⁴⁾

Tau protein is a highly soluble microtubule-associated protein (MAP). In humans, these proteins are found mostly in neurons compared to non-neuronal cells. One of the tau's main functions is to modulate the stability of axonal microtubules. Other nervous system MAPs may perform similar functions, as suggested by tau knockout mice that did not show abnormalities in brain development - possibly because of compensation in tau deficiency by other MAPs. Tau proteins interact with tubulin to stabilize microtubules and promote tubulin assembly into microtubules. Tau has two ways of controlling microtubule stability: isoforms and phosphorylation.

FORMATION OF TAU PROTEINS:

Neurofibrillary tangles are obtained by hyperphosphorylation of a microtubule-associated protein known as tau, causing it to aggregate in an insoluble form. They are also referred as PHF (Paired Helical Filaments). The precise mechanism of tangle formation is not completely understood, and it is still controversial whether tangles are a primary causative factor in disease or play a more peripheral role.

CAUSES:

Tau is a substance that destroys the brain cells necessary for learning and memory leading to Alzheimer’s disease. The elevated activity of enzymes that act on tau is known as tau kinase that cause tau protein to misfold and clump forming neurofibrillary tangles.

MECHANISM:

The Aβ peptide is produced from the larger amyloid-β precursor protein (APP) through two sequential enzymatic activities, β- and γ-secretase. β-Secretase activity (more often than not attributed to the BACE1 protein in the brain (5)) is commonly thought of as the rate limiting enzyme in Aβ production.β-Secretase activity leaves a membrane bound C-terminal fragment which is then cleaved by γ-secretase. This final cleavage generates the secreted Aβ peptide and a cytosolic fragment which may offer a clue to the actual function of APP ^{(6) (7) (8)}. The majority of Aβ is 40 amino acids long (Aβ₄₀), but a small proportion (<10%) is slightly longer (Aβ₄₂). Higher levels of Aβ₄₂, the more hydrophobic and fibrillogenic form of the peptide, fosters the assembly of Aβ into progressively higher order structures, from dimers all the way up to the insoluble plaques that finally deposit in the brain ⁽⁹⁾. Since the more soluble assembled forms of the peptide are directly toxic ⁽¹⁰⁾, as the total amount of Aβ increases, neurons and synapses start to suffer deleterious consequences and, ultimately, degenerate ⁽¹¹⁾.

INHIBITION OF TAU PROTEIN:

Natural remedy to inhibit this protein shows activity on Cinnamon which has two compounds in it. They are cinnamaldehyde and epicatechin that can perhaps prevent the accumulation of tau protein with the highest inhibitory effects in it. The compounds present in the cinnamon will prevent the clumps or tangle formation in the brain that leads to Alzheimer’s disease.

The enzyme which inhibits the symptoms of Alzheimer’s by interfering with the action of another problem protein, called beta-amyloid. Like tau, clumps of this protein accumulate in the brains of people with Alzheimer’s, making it another suspected cause of the disease.

When beta-amyloid forms these sticky plaques, it can likewise change the structure of the tau proteins, causing them to become toxic and form tangles. But Ittner’s team found that p38γ kinase makes a different kind of structural change to tau. If this change is made first, it prevents beta-amyloid from being able to turn tau bad, and mice do not develop Alzheimer’s-like symptoms. In people, the levels of this enzyme decline significantly as Alzheimer’s progresses, hinting that boosting this enzyme could help prevent or treat the disease.

DRUGS TO TREAT TAU PROTEINS:

Tau protein is the chief component of tangles, the other hallmark brain abnormality of Alzheimer’s. Tau protein helps maintain the structure of a nerve cell, including tiny tube-similar structures called microtubules that deliver nutrients throughout the nerve cell.

Tauprotein: AADvac1 AADvac1 is a vaccine that stimulates the body’s immune system to attack an abnormal shape of tau protein that destabilizes the structure of nerve cells.If successful, it accepts the potential to help halt the advance of Alzheimer’s disease. A phase 2 clinical trial enrolling 185 volunteers with mild Alzheimer’s disease began in March 2015 and is expected to be completed in February 2019. (The drug is still in research; not available to the public.) Beta-amyloid is the chief component of plaques, one hallmark Alzheimer's brain abnormality. This includes blocking activity of beta-secretase enzyme; preventing the beta-amyloid fragments from clumping into plaques; and even using antibodies against beta-amyloid to clear it from the brain.

Beta-amyloid: Solanezumab:

Solanezumab is a monoclonal antibody designed to bring down the degree of beta-amyloid in the genius. The antibody binds to beta-amyloid, preventing the formation of plaques; solanezumab may also help carry excess beta-amyloid away from the brain.

Beta-secretase (BACE) is unitary of the enzymes that clips APP and makes it possible for beta-amyloid to form. Therapies that interrupt this process may reduce the amount of beta-amyloid in the brain and ultimately intervene in the development of Alzheimer’s disease.

Beta-secretase:

Verubecestat Verubecestat is a BACE inhibitor- it suppresses the ability of the beta-secretase enzyme to produce beta-amyloid.

Inflammation in the brain has long been known to play a role in the changes that occur in Alzheimer’s disease. Both beta-amyloid plaques and tau tangles cause an immune response in the brain and microglia cells act as the first form of immune defense against them. Yet, while microglia help clear beta-amyloid in the psyche, they can become overactive in the presence of plaques and produce compounds that damage nearby cells.

Inflammation:

CSP-1103 CSP-1103 (also known as CHF 5074) is a microglial modulator that aims to reduce inflammation in the brain.

The 5HT6 receptor found in some brain cells can lock in chemicals called neurotransmitters. This lessens the quantity of neurotransmitters available for the brain to use for communication between nerve cells (nerve cells). Only through neuron-to-neuron communication can an individual think and function normally. Acetylcholine is one of these neurotransmitters. People with Alzheimer’s disease have low levels of acetylcholine. Blocking the 5HT6 receptor may increase the amount of acetylcholine and help nerve cells to maintain normal communication.

5HT6: Intepirdine Intepirdine is a 5HT6 receptor antagonist that blocks the receptor’s ability to decrease acetylcholine levels. A phase 3 clinical trial of Intepirdine began in October 2015 with a goal of recruiting 1,150 people with mild-to-moderate Alzheimer’s disease.

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Received on 29.07.2017 Modified on 18.11.2017

Research J. Pharm. and Tech 2018; 11(2):788-790.

DOI: 10.5958/0974-360X.2018.00149.X