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Tau, a small three-letter word with vast consequences. A protein which if dysfunctional, can contribute to the development of Alzheimer’s disease, the most common form of dementia affecting over 520,000 people in the UK . I’m sure many of you are aware of Alzheimer’s, and may even know someone affected by it, but it is possible that you haven’t heard of the tau protein. So, what is it, and how can one protein cause such devastating harm to the brain?
The tau protein is a microtubule-associated protein. This means tau binds to microtubules (part of the cell’s cytoskeleton involved involved in cell shape, and transport within the cell) to stabilise them. Tau is especially abundant on the microtubules within nerve cells, and are important in maintaining normal neuronal cell function. For this reason, when their functioning goes wrong, they have such calamitous effects on brain functioning.
The binding of tau to microtubules is regulated by phosphorylation. This is the process by which a phosphate molecule is added or removed from the tau protein by kinase and phosphorylase enzymes respectively. In Alzheimer’s however, the tau protein is hyperphosphorylated, meaning it is phosphorylated more than it should be. This results in the tau protein forming clumps, termed ‘neurofibrillary tangles’ or ‘plaques’. These plaques are insoluble, meaning the they persist and lead to limited transport within the neurone. This can lead to death of the neurone, or in other words Alzheimer’s .
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Amyloid beta is another important protein involved in the development of Alzheimer’s. Its normal function within the brain is not understood completely, although some studies have suggested that it plays a role in enzyme activation and cholesterol transport . It is essential for proteins to evolve functions within an organism in order for the gene to be selected for, and passed onto the next generation. Many proteins and their genes that have negative effects on organismal functioning are often selected against, gradually de-evolve and are lost from the genome. This therefore begs the question of how the amyloid beta protein has evolved, if it is one of the main pathological factors for Alzheimer’s and doesn’t appear to have a clear physiological function. It is possible that, because in many cases, Alzheimer’s doesn’t develop until later on in life, the faulty amyloid beta protein is passed onto offspring as individuals are able to pass these genes on in early life before the symptoms of Alzheimer’s take hold.
The amyloid beta protein is synthesised from amyloid precursor protein (APP), which is cleaved by beta secretase and gamma secretase enzymes to produce the mature amyloid beta protein . This process however is a necessary evil, as it is these enzymes which, if mutated, can give rise to amyloid beta proteins which, similarly to tau, clump together to form amyloid plaques. These plaques, again like tau, can cause neuronal death and subsequent cerebral deterioration.
So, how can the amyloid beta protein become pathogenic? As I mentioned, it is the enzymes that create amyloid beta that mutate and cause amyloid plaques. The gamma secretase enzyme is, in part, controlled by the PSEN1 gene, and it is this very gene, which can mutate and give rise to amyloid plaques in the brain .
Another gene which gives rise to the faulty form of the amyloid beta protein is the mutant APP gene. This gene codes for the amyloid beta precursor protein, which, as the name suggests is the protein which when cleaved by enzymes gives rise to the mature amyloid beta protein. It has been speculated that there are over 50 types of mutations in the APP gene which can cause the early-onset of Alzheimer’s . One of the most common forms of these mutations is one in which the amino acid valine is replaced by isoleucine. This leads to the over synthesis of amyloid beta, or synthesis of a ‘sticker’ form of the protein which causes amyloid beta proteins to clump together .
Now to summarise the key points. Tau and amyloid beta proteins are two of the main proteins involved in the development of Alzheimer’s, and both when mutated, form plaques that can lead to neuronal death and the memory loss and confusion which is so typical in Alzheimer’s patients. So, now we know some of the primary causers of Alzheimer’s, how has this knowledge been used to combat the disease?
Unsurprisingly, drugs that decrease the production of amyloid beta are an effective way to reduce the amyloid plaques that form in the brain. These drugs target the enzymes that convert amyloid precursor protein to amyloid beta, including gamma secretase. Termed ‘secretase inhibitors’, these drugs block the action of the enzymes that synthesise amyloid beta and thus are effective in alleviating the effects of the amyloid plaques .
You will remember the tau tangles, which, similarly to amyloid beta, form plaques in the brain and inhibit nerve cell functioning. Predictably, the tau protein has also been a target for drug companies trying to battle Alzheimer’s. Research published this year has shown that a drug named LMTX (second-generation tau aggregation inhibitor) has shown a reduced shrinkage in brain size in patients suffering with mild Alzheimer’s by tackling the tau plaques. Despite this, the phase III clinical trial proved to be negative, because the drug failed to improve cognition and memory in those 891 people tested .
As of yet, there is no complete cure for Alzheimer’s. But with research continually progressing in this field, let us hope that in the not too distant future, treatments or preventative medicines will be readily available.