Tau Proteins and Alzheimer's disease

The writer and the graphic designer: Beshoy Emad Milik

"Hey grandma, I really miss you so much," said the Child.

"Hello, my dear ... Alex... I mean Alfred... Um... Umaa..." said grandmother.

"It is Albert, Grandma," said the Child.

Isn't it frustrating to see your beloved ones losing the most precious thing they own? Unintentionally, they lose a valuable and vital component of their lives. The memory that makes us who we are. That’s because it represents the sophisticated ability to remember many details that are in desire, daily. And for sure, it is a tremendous biological database where we store our victories, achievements, The names of our friends and much more.

You can imagine how disrupting it is for a person's memory breaks down and nothing to be left but rags. Alzheimer is the name given to the disease that causes degeneration of the brain and memory decay.

In some cases of Alzheimer's disease (AD), the cause is a mutation of the genes such as APP (amyloid precursor proteins) on chromosome 21, presenilin 1 on chromosome 14 and presenilin 2 on chromosome 1. It results from pathological deposits of extracellular amyloid proteins in the cerebral cortex or intracellular Neurofibrillary Tangles (NFTs) containing tau proteins.

Many of you, in the medical field, may have heard of amyloid proteins, but tau proteins may seem probably vague. Interestingly, for its therapeutic values proved by clinical trials, it is the tau protein that matters.

Tau proteins: physiology and pathological facts

Tau is a protein associated with microtubules (a component of the cellular cytoskeleton) that is found, predominantly in neurons of the central nervous system (CNS) and it may be present at low levels in astrocytes and oligodendrocytes.

First discovered in 1975, it was shown to play an essential role in the stabilization and function of neuronal microtubules. Subsequently, it is involved in numerous vital processes such as cell signaling, synaptic plasticity and regulation of genomic stability.

Tau proteins undergo many post-translational modifications such as acetylation, glycation and especially phosphorylation. There are over 80 phosphorylation sites on tau molecules.

Hyper-phosphorylation of the tau molecules decreases their binding affinity to microtubules, which lead to disassembly and detachment. These free detached molecules have an affinity for each other. They aggregate and form misfolded tau Oligomers. Oligomers then gain more units and deposit forming Neurofibrillary Tangles (NFTs) also called Tau Inclusions that lead to neuronal loss.

Subsequently, this leads to several harmful consequences including: axonal impairment, alternation of synaptic structure, mitochondrial dysfunction and ineffective protein degeneration collectively called tauopathies.

In Alzheimer's disease, NFTs are initially deposit mainly in the perikaryon (somato-dendritic part) of neurons. Then, they spread through a prion-like mechanism from a nerve cell to another. It is possible to reach distant areas of the brain such as the hippocampus.

Immunotherapy: A New hope for memory decay

Nevertheless, scientists recently have been through dozens of research trials finding the best treatment for AD. They came up with a very thrilling conclusion. Immunotherapies aimed at preventing beta-amyloid plaques formation lack significant cognitive improvement in humans.

On the other hand, targeting tau proteins are currently under trails giving better significant results. Histological analysis and Tau positron emission tomographic studies have shown that cognitive impairment correlates more strongly with tau than amyloid-beta.

However, it is not that easy to target tau proteins with all post-translational modifications that can alter the binding of antibodies to specific regions of the tau molecules. In addition, antibodies affinity would be dependent on the structural orientation assembly, i.e., monomers, dimers, oligomers, fibrils or NFTs.

Immunotherapy targets and blocks tau-mediated toxicity by several mechanisms:

a) direct inhibition of pathological aggregation.

b) Inhibition of post-translational modification.

c) Inhibition of tau propagation

d) Stabilization of microtubules.

The most efficient method is inhibition of pathological aggregation.

Active immunotherapy techniques are used by vaccination of specific pathological forms of hyper-phosphorylated tau. Thus, this prevents activation of B or T cell response against physiological functioning tau in the host with sustained immunity for prolonged periods. However, some scientists reported brain encephalitis in mice.

Passive immunotherapy might be more attractive, but could also target physiological forms. For either technique, crossing the blood-brain barrier to access the neurons would not be a problem, as it is already impaired in AD patients.

Results of both techniques are very promising according to many papers. Fortunately, they met the standards of safety and efficacy and passed phase I trials. Many phase II trials are held to date.

Thus, are we few steps away from a novel treatment of Alzheimer's disease? Are humans going to succeed in their battle to keep their memories intact against this degenerative disease? We hope so, for the good of mankind.

References:

1. Oxford handbook of medical neurology.

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