...palliative while more potent drugs have encountered problems during clinical trials. It is known that the disease results from brain deterioration associated with the formation of microscopic lesions. Genetic mutations cause a small minority of cases but our knowledge of the underlying biological mechanisms is limited. The key to improved understanding may be a process vital to brain cells called axonal transport. Disruption of axonal transport seems to be an early event in the progression of the disease and is linked to lesion formation and brain dysfunction so a full investigation of this process should lead to a cure, if not prevention.

Keywords: Alzheimer's disease, axonal transport, kinesin, microtubule, amyloid hypothesis, tau hypothesis

Alzheimer's disease: a growing scourge

The population is increasing and we are living longer but not necessarily healthier lives: more of us are suffering disease and infirmity in old age. One particularly distressing set of late-onset diseases is dementia. It is estimated that over 20 million people suffer dementia worldwide, about 700,000 in the UK. The serious impact of dementia on families and society is increasing as these Figures are expected to double every 20 years. In the UK, the current cost of care alone is calculated at over 17B [pounds sterling] per annum while the annual death toll is over 60,000. The majority of dementia sufferers have Alzheimer's disease (AD) (1).

Following initial diagnosis of AD, the individual endures (on average) 8 years of increasingly distressing and decreasingly manageable symptoms as their brain decays. The billions of specialised cells of the brain that enable our cognitive faculties are called neurons (or neurones). They interconnect via synapses to form the complex neural network of the brain. The disease initially destroys synapses then kills neurons; the damage spreads out from the interior of the brain to the surface: from the basal forebrain through the hippocampus to the cortex (2). It is estimated that neurodegeneration starts more than 20 years before symptoms become apparent (3).

The first symptoms, notably abnormal memory deficit, are accompanied by a reduction in the normal production of the neurotransmitter acetylcholine. Neurotransmitters are the chemicals that nerve cells use to communicate with one another. Drugs have been developed to compensate for this decline but Mount and Downton (4) note that "... none of the currently approved drugs stops the underlying degeneration of brain cells or reverses the progression of Alzheimer disease."

This paper outlines our current knowledge of AD, recent advances towards a cure, and the role of axonal (axoplasmic) transport in normal and diseased brains.

Two types of Alzheimer's: familial and sporadic

The familial form of AD is estimated to account for less than 5% of all AD cases and is normally early-onset i.e. most cases present before the age of 65. It is identified with specific genetic mutations affecting amyloid precursor protein (APP), presenilin-1 (PS1), and presenilin-2; most cases have the PS1 mutation. The main constituent of senile plaques, amyloid-[beta], is produced by the sequential cleaving of APP by [beta]-secretase and [gamma]-secretase. Presenilin is a component of [gamma]-secretase. Faulty processing of APP is therefore suspected of causing familial AD (3).

[FIGURE 1 OMITTED]

The common, sporadic form of AD is late-onset: incidence rises steeply with age after 65. Sporadic AD doesn't correlate with any of the familial-form genetic mutations though there is a genetic link: a mutation in the gene for apolipoprotein E that is thought to compromise the protein's neuroprotective function. This mutation, however, is not a determinant but a risk factor for the disease; the cause of sporadic AD remains to be discovered (3).

Shrunken brain with lesions

Dementias result from the dysfunction, degeneration and loss of neurons in the brain. The most obvious characteristic of a postmortem AD brain is massive neural atrophy (Figure 1).

Microscopic examination of stained sections of AD brain reveals the presence of myriad extracellular senile plaques and intracellular neurofibrillary tangles, significantly more than observed in normal brains of the same age (5). The processes governing the formation of these inclusions, the toxicity of the various intermediates in their formation and their mechanisms of damage are under intensive study.

The presence of plaques and tangles has given rise to two hypotheses as to the cause of this devastation: the amyloid hypothesis and the tau hypothesis respectively. To what extent either hypothesis is correct remains to be demonstrated.

Amyloid hypothesis

The amyloid hypothesis proposes that AD is caused by genetic mutations or environmental factors which favour the production...

NOTE: All illustrations and photos have been removed from this article.



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