Cures for Alzheimer's may come from understanding its chemistry. Arvi Rauk of the University of Calgary, Canada, examines the disease at the molecular level

Alzheimer's disease is a devastating, fatal, neurological disorder with no known cause and no cure. Primarily a disease of old age, it has become a very serious problem as general life-expectancy has increased. The afflicted person suffers progressive loss of memory and thinking ability, mood swings, personality changes, and loss of independence. 

Physically, Alzheimer's is characterised by massive loss of neurons and disrupted signalling between cells in the brain. The disease can be diagnosed post mortem by observing tangles inside and senile plaques outside cells throughout the brain. The major component of the plaques is a small, 40- or 42-amino acid peptide: amyloid beta (A). That A is a causative agent in Alzheimer's was first suggested as the amyloid hypothesis about 15 years ago and is now widely accepted. Uncovering the chemistry associated with A is crucial to understanding Alzheimer's progression and may shed light on the cause or causes. 

A is an elusive entity whose chemical and biological actions have been difficult to fathom. It does not crystallise, is not very soluble, and has a highly changeable structure in solution. On incubation, it does form ordered fibrils that can be analysed by nuclear magnetic resonance analysis. Whilst the structure of the toxic species has not been established, the peptide is known to be at its most damaging in aggregates of two or more. Therefore the fibril structures can provide clues about the nature of the toxic aggregates. 

A binds strongly to copper(II) ions in the body through its three histidines and the resulting copper-A complex is a moderately strong oxidising agent. It is readily reduced to the copper(I) form by vitamins C and E and other reducing agents, possibly including the peptide's single methionine group. In the reduced form, the copper-A complex can generate destructive species such as hydrogen peroxide, hydroxyl radicals, and other reactive oxygen compounds. Since A is generated from a transmembrane protein it - and its copper complexes - inherits an affinity for cell membranes from its parent. Therefore the copper(I)-A complex may generate radicals near the highly unsaturated lipid bilayers that make up membranes in the brain, resulting in extensive membrane damage through lipid peroxidation. In addition, A aggregates can form membrane-penetrating holes that allow ions to pass into and out of brain cells unregulated, including across the protective blood-brain barrier.

In addition to copper and itself, A binds to numerous other proteins, all with deleterious consequences. For instance, interaction with nervous system protein tau results in nerve cell collapse; binding to catalase causes the enzyme to lose its hydrogen peroxide clearing function; interaction with apolipoprotein E accelerates the aggregation of A itself into toxic species. When A interacts with insulin receptors in nerve cells it causes reversible memory loss and diabetes symptoms.

So, are there any drugs available that can prevent Alzheimer's? The answer is not yet, but luckily, the likelihood of contracting Alzheimer's can be reduced by some statins and non-steroidal anti-inflammatory drugs. Antioxidants such as those found in red wine may also be effective. Since A is the culprit, some pharmaceutical companies are seeking to block the enzymes responsible for forming the peptide or to promote enzymes that can degrade A into smaller harmless pieces. Others are seeking compounds that can prevent its aggregation process, or reverse it. 

The past decade has seen significant advances in our understanding of A neurotoxicity mechanisms and this has spawned a new generation of drug candidates that should lead to prevention of the disease. In my optimistic opinion, these approaches will meet with success sooner rather than later. 

Read more in the critical review 'The chemistry of Alzheimer's disease' in Chemical Society Reviews.

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