Alzheimer’ Disease

The graying of hair, the slow but steady appearance of ugly wrinkles all over the body, one by one loss of all teeth and decline of general vigour and exuberance of the bygone days, are not the only horrifying signals of advancing age, for a chronic dementing illness may also raise its ugly head as one grows older. Throughout the world, about 10 per cent of the people in their 70s and 40 per cent in their 80s suffer from a progressive deterioration of intellect, memory and thought, popularly known as Alzheimer’s Disease (AD). It is named after a German doctor, Alois Alzheimer who first described this disease in 1907.

A major public health problem, AD deprives its victims of cognitive abilities. The distressing nature of this disease is reflected in memory loss that makes even day-to-day skills like typing shoelaces, pouring tea or buttoning a shirt very difficult for its victims. As the victim drifts away from performing the normal basis personal needs, the disease affects adversely his personality and social behaviour. It then shows up as a major psychiatric disorder. At this terminal stage, the patient becomes mute, beset with several neurological abnormalities such as seizures and is completely bed ridden.

The onset of AD is so gradual that doctors miss it at its early stages. The disease becomes apparent only when mental derangement becomes marked and the person’s behaviour turns to abnormal. It can only be diagnosed at early stages after examination of the brain tissue. More recently, however, advances in medical technology have given birth to new imaging techniques such as Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET), which permit visualization of changes in the brain structure making early diagnosis easier.

Shaking the earlier belief that AD is due to hardening of blood vessels or haemorrhages in the brain, Alois Alzheimer showed two characteristic lesions, clearly visible, in the brain of persons who died of this disease. Spread diffusely throughout the cerebral cortex and hippocampus regions of the brain of Alzheimer’s victims are present small spherical structures known as ‘senile plaques’ and minute bundles of abnormal thread-like protein material called Neurofibrillary Tangles (NFTs). The plaques have a central core made of protein called beta-amyloid which is surrounded by degenerating nerve cells. The amyloid protein is fibril-like in nature. Although research studies have suggested that this protein is formed even in the normal, healthy brain cells, it is still unclear as to why it gets deposited as senile plaques in the brain of Alzheimer’s victims and not in normal persons.

Beta-amyloid is a small protein containing just 42 amino acids, the building blocks of a protein molecule. It is, however, made from a larger molecule, the Amyloid Precursor Protein (APP). The latter, apparently, does not harm the cells as it is found even in normal brain cells. The problem arises only when beta-amyloid is clipped out of APP by some protein-splitting enzymes. But, in principle, this should not happen as APP is embedded in the cell membrane with only about two-thirds of beta-amyloid segment jutting out on the cell’s exterior while the rest remains buried in the cell membrane, thus escaping the effect of protein-splitting enzymes. Normally, in healthy individuals, the outer APP segment is clipped off from the membrane and secreted out of the cell. In other words, the cell is not able to produce beta-amyloid. In the unfortunate victims of Alzhiemer’s Disease, a biochemical reaction occurs which makes possible the production of beta-amyloid protein.

The biochemical anamoly that leads to the production of beta-amyloid has been discovered. This finding suggests that cells have alternative ways of breaking down APP which may yield intact beta-amyloid fragments. This actually occurs in small vesicles of the cells called lysosomes, which are loaded with enzymes capable of cleaving just any bond in a protein. But why should the normal pathway of degradation of APP shift to such alternative pathways? One plausible reason is the presence of some inherent defect in APP. the puzzle was solved in 1991 when John Hardy, a neurogeneticist at St. Mary’s Hospital Medical School, London, reported that a genetic alteration of a mutation occurs in the gene encoding APP. This gene has been traced to a location on chromosome 21.

Interestingly, victims of a genetic disorder called Down’s Syndrome who have an extra chromosome 21, usually develop beta-amyloid deposits in the brain cells and exhibit dementia similar to AD. The mutation in APP gene seems to predispose its carries to AD. This is evident because in several families AD is inherited by one generation from the other. Whether it is a single gene that mutates or a whole lot of genes cause AD is yet not clear. Besides, influence of environmental factors are also not discounted. The defect may even lie in the enzyme that splits the APP during its normal processing.

The second prominent changes seen in the brains of Alzheimer’s victims is the presence of NFTs, the rope-like filaments comprising two fibres twisted about each other. Though common in many diseases of the brain, NFTs are completely absent in healthy brains. These tangles severely inhibit the passage of nerve impulses from one brain cell to the other. This occurs due to destruction of synapses, the special connections between two nerve cells where one neuron ends and joins hands with the other forming a chain. Many such connections give rise to a neural network that is central to many brain functions, including memory and thought process. The neural message that is transmitted from one nerve cell to the other is actually facilitated by a chemical compound called neurotransmitter.

Normally, a protein named “Tau’ forms a complex network, the cytoskeleton, in the cytoplasm of nerve cells and coordinates the movements of various molecules within it. If the cytoskeleton is disrupted, the cellular transport fails. In AD, the tau-protein is not the same as normal brain cells. It is modified with additional phosphate molecules tagged to it. The alteration in the structure of tau destroys its ability to form the assembly of the cytoskeleton. It eventually robs the brain cells of the ‘highways’ which are indispensable for ferrying the neurotransmitters and many other protein molecules to and fro the nerve cells through synaptic connections. As a result, the neurochemicals get piled up in the brain cells. Moreover, NFTs also deplete acetylcholine and norepinephrine that play an important role in communication between the nerve cells. All these contribute to the development of abnormal physiological changes.

Scientists even believe that certain neurotoxic substances present in plants may have a hand in leading the brain to such devastation. The exposure to these neurotoxins early in life may be damaging the brain which becomes visible only after many decades. Reports of high levels of aluminium in the brain cells of Alzheimer patients have intrigued scientists as to whether this element is the cause of the damage or just one of the products that appear as the disease advances. Another hypothesis on the cause of AD spawns from the fact that certain progressive diseases of the brain result from infectious agents such as a virus. Besides, there is also a speculation that chronic activity of body’s defence machinery, such as in repeated infections, could lead to brain damage. All these put together suggest that the disordered chemistry of the brain cells in AD is due to complex interaction of several factors, as no definitive cause has yet been unearthed.

Meanwhile, efforts are in full swing for tackling the symptoms of AD, namely, depression, agitation and psychotic behaviour. However, the need of the hour is to devise a therapeutic strategy that could block the biochemical events associated with the formation of senile plaques and NFTs—the visible lesions—in the brain cells. Drug which can enhance the production of neurotransmitters, such as acetycholine are being tested for their suitability in treating the disease. One such candidate drug, physostigmine, is very promising. Studies have shown that long-term administration of this chemical slows down brain damage. Yet another rationale suggests transplantation of active brain tissue taken from aborted human fetuses. This is thought to promote the regeneration of nerves and revival of the brain’s functions in such patients. The practicality of this surgical therapy is rather doubtful since wide regions of the brain are affected in AD.


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