Development of Alzheimer’s Disease – Is Tau Protein to Blame?

Thanks to the progress of medicine, these days we live much longer than just few decades ago. However, we don’t become healthier as we age. In the rapidly aging population, the problem of dementia is becoming particularly acute.

In the majority of cases, dementia is associated with Alzheimer’s disease. This neurodegenerative disorder affects an estimated 35 million people worldwide and caring for Alzheimer’s patients was estimated to cost the world $604 billion in 2010 alone.

Millions of dollars are being spent worldwide to study the disease, and although some treatments are available to reduce the symptoms, median life expectancy after the diagnosis is only seven years. Partially this lack of progress is a result of our poor understanding of this condition and neurological mechanisms behind its development.

The typical pathological features of the disease were first described by Dr. Alois Alzheimer in 1907. Post-mortem examination of the brain of his patient, 55-year-old Auguste Deter, revealed abundant plaques and neurofibrillary tangles. Both formations are caused by an abnormal aggregation of certain proteins. Amyloid plaques are formed outside the neurons from the insoluble dense deposits of beta-amyloid peptides. Neurofibrillary tangles are insoluble twisted fibers that are formed inside the cells as a result of aggregation of another protein called tau. Both plaques and tangles are considered hallmarks of Alzheimer’s disease, and both receive the intense attention of researchers trying to find out how they affect the processes in the brain.

Two major theories were formulated by scientists in an attempt to explain the development of disease. They are known as amyloid hypothesis and tau hypothesis. As the names suggest, the hypothesis consider the corresponding proteins as major players in the disease development.

Historically, amyloid hypothesis was suggested first. Amyloid plaques are larger and more obvious formations, and possibly this is the reason that researchers initially focused predominantly on this pathological feature of Alzheimer’s disease. Although lots of research time and money were spent on studying the plaques and their role in the disease, some important questions remained unanswered. First, the plaques are located outside of brain cells in the extracellular space. With such locations, it is not clear how they can affect the function of these cells and cause their eventual death. Second, it is not unusual to see lots of plaques in the brain of cognitively normal elderly people. Why are their brains unaffected by the plaques?

More recently, neurofibrillary tangles attracted more attention as potential causative agents of Alzheimer’s disease. There are good reasons to support this line of thinking. First, the clinical stages of cognitive decline much better correlate with the number, density and distribution of tangles. Second, there is more clarity in regards of how the tangles affect the brain cells. Tangles are located within the cells and affect the cell’s transport machinery which eventually results in the inability of the cell to perform its normal functions. Third, tangles are more common in the brain regions associated with memory.

These observations gave strength to the tau hypothesis which blames the formation of neurofibrillary tangles for the progression of Alzheimer’s disease.

Very recently, it was demonstrated that the agglomerates of tau proteins can be transported from one nerve cell to another along the neural network of axons connecting these cells. These agglomerates act as “seeds” for the formation of new tangles at new locations. In theory, once the protein aggregates are formed, they can spread around the brain like infectious agents, using the very same cell transportation system that they are going to destroy.

Tau hypothesis also doesn’t explain everything, however. The formation of tangles is often observed in the brain of people as young as thirty years of age. Apparently, there are some processes and mechanisms that can eliminate the tangles or prevent them from affecting the brain functions.

These days, many researchers tend to consider Alzheimer’s an aging-related breakdown of neuronal pathways. It can be accelerated or caused by certain events such as head injury, genetic predisposition, some diseases and so on, but in general the process is not out of line with normal phenomena observed in the aging brain. Both plaques and tangles are the products of this process, rather than causative factors. Once they are formed in sufficient quantities, however, they start to spread along the neuronal pathways, eventually causing the observed symptoms of the disease.

Clear understanding of what’s going on in the brain when it’s affected by Alzheimer’s disease is critical if we ever want to get the drugs for treatment of this condition. The new view on the pathogenesis of Alzheimer’s disease may indicate that targeting the plaques and tangles with various drugs is a rather futile exercise. We should look for the processes leading to their formation in the first place. Once these processes are clearly understood, suitable therapeutic targets for the drugs will become obvious.

It seems that some progress has already been achieved – several drugs targeting the process of tau agglomerate formation are being investigated now. But the trials take many years. Unfortunately, if Auguste Deter, the first documented Alzheimer’s patient, was diagnosed with her disease today, more than a century later, her prognosis wouldn’t be much different.


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Image via Fotoluminate LLC / Shutterstock.

Viatcheslav Wlassoff, PhD

Viatcheslav Wlassoff, PhD, is a scientific and medical consultant with experience in pharmaceutical and genetic research. He has an extensive publication history on various topics related to medical sciences. He worked at several leading academic institutions around the globe (Cambridge University (UK), University of New South Wales (Australia), National Institute of Genetics (Japan). Dr. Wlassoff runs consulting service specialized on preparation of scientific publications, medical and scientific writing and editing (Scientific Biomedical Consulting Services).
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