Contents

Notes from the PDSG AGM, March 2001

Tau is a protein that is a normal component of the brain and is essential for neurones (brain cells) to function properly. The human body is made up of billions of different cells, and each cell contains thousands of different proteins. Some proteins carry out the chemical reactions required for the cell to function properly, these are called enzymes. Other proteins have structural roles, for example they are used to make hair or fingernails, or are used to form a ‘scaffold’ which gives individual cells their characteristic shape. The tau protein is one such scaffold protein in brain cells. The tauopathies are a group of diseases in which the tau protein is involved. The tauopathies include diseases such as Pick’s disease, progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), as well as the only recently described genetic or inherited condition called frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Collectively, Pick’s disease, PSP, CBD and FTDP-17 are sometimes referred to as frontotemporal dementias (FTDs), a reflection of the specific area of the brain they usually affect. Alzheimer’s disease (AD) is also sometimes regarded as a tauopathy since the tau protein is involved in its progression, although in this case other proteins in addition to tau are also very important.

Approximately 7% of the population over 65 years of age currently develop a neurodegenerative disorder, with frontotemporal dementia accounting for about 10% of these cases at 65 years of age. AD accounts for the majority of the rest of the cases. Very importantly, because AD and the FTDs are tauopathies, research into any of these disorders is relevant to understanding any or all of the other conditions. That is to say, research into the functions of (and indeed dysfunctions of) the tau protein is informative about the disease process in any of the tauopathies. So research into the role of tau in AD may also tell us something about what is happening in, for example, Pick’s disease; an understanding of one disorder can lead to a better understanding of a related disorder. With this realisation in mind, we see that advances are being made in the understanding of rarer neurodegenerative conditions in the tauopathy family, which may on the face of it appear to be under-researched.

Treatments or therapies for disorders such as the tauopathies will only be effectively developed with a precise understanding of the biochemical changes that cause these conditions, and this can only be gained through biomedical research. The immense costs associated with neurodegenerative disorders should always be viewed not just in the context of the financial costs to the state, but also in the emotional costs to families and carers. Since the single major risk factor for disorders such as AD is old age, and also as life expectancy continues to increase and the size of the ageing population expands, our society will face enormous problems in the next 20-30 years in dealing with the millions of people who will be affected by these diseases. Biomedical research offers a ‘common sense’ approach to help minimise the costs of these devastating conditions.

So what does the tau protein normally do, and what goes wrong in the tauopathies? Well the brains of patients with tauopathies are characterised by the abnormal accumulation of tau protein in ‘lesions’ (sometimes called ‘aggregates’) inside neurones. In AD these tau lesions are called ‘neurofibrillary tangles’, and they co-exist with another type of lesion called the ‘senile plaque’ which contains a different protein, called beta-amyloid. There is currently great debate in the scientific community about whether senile plaques or neurofibrillary tangles are most important in AD. In Pick’s disease, the lesions are a little bit different – these are called ‘Pick bodies’. But like AD neurofibrillary tangles, the principal constituent of Pick bodies is a form of the tau protein. It is noteworthy that studies of FTDs have already been very informative in AD research, since unlike AD brains, FTD brains show only tau-containing lesions. As Pick’s patients clearly suffer from dementia, we can conclude that tau protein alone is in some cases sufficient to cause dementia, suggesting that in AD the formation of neurofibrillary tangles may be more relevant than the formation of senile plaques.

Tau is what we call a ‘microtubule-binding protein’. Microtubules are filaments within the neurone, which give the cell its characteristic shape and are involved in the transport of cellular chemicals. Tau deposition in lesions ultimately leads to dementia since these aggregates cause the neurones to die, and in the adult brain these neurones cannot be replaced. This loss of neurones causes the disease symptoms. The tau which deposits in diseased brains turns out to be chemically altered compared to normal tau, and this alteration is termed ‘phosphorylation’. Tau altered in this way does not bind to microtubules properly and instead forms the aggregates, which are seen as lesions at post-mortem. Just why this abnormal tau forms is still unclear. What we do know is that there are in fact subtle differences in the nature of the tau deposited in the different tauopathies. The gene that expresses human tau is carried on chromosome 17, and is able to produce six different forms of the tau protein, three of which are called ‘long tau’ and the other three ‘short tau’. AD neurofibrillary tangles contain all six forms, while Pick’s disease Pick bodies contain only the short forms and CBD/PSP lesions contain only the long forms. Currently we do not know why different tau proteins deposit in different diseases. Very recently, a small number of familial or inherited forms of FTDs have been shown to be caused by ‘mutations’ in the tau gene. These mutations, in the condition FTDP-17, lead to the formation of mutant or faulty tau protein which forms aggregates more quickly than normal tau. This genetic evidence is very important and finally conclusively shows that dysfunction of tau protein can directly cause neurodegenerative disease. Some 20 different tau mutations have now been identified in 50 families worldwide, and interestingly some mutations produce AD-like changes, whilst others produce Pick-like or PSP-like pathology. Consequently, it is likely that some of the familial diseases previously diagnosed as Pick’s disease were probably actually FTDP-17. Precise pre-mortem diagnosis of tauopathies will become increasingly important as new potential therapies become available in the next few years. Currently strategies, which might prevent the abnormal phosphorylation of the tau protein, or prevent its aggregation in to lesions, as well as other approaches to restore the neurotransmitter deficits which occur because of neuronal loss, are among the potential therapies for the tauopathies currently being pursued by the pharmaceutical industry.

Abbreviations used
PSP - progressive supranuclear palsy
CBD - corticobasal degeneration
FTDP-17 - frontotemporal dementia and Parkinsonism linked to chromosome 17
FTDs - frontotemporal dementia
AD - Alzheimer’s disease

Dr. Robert Layfield