New target found in search for Alzheimer's treatment

Researchers hunting the serial murderer responsible for the progressive, mass-death of neurons in Alzheimer's disease, the most common form of dementia, have found a new suspect.

More accurately, it is multiple alter-egos of the prime suspect, amyloid plaque, the tiny protein deposits that clog neural tissues in Alzheimer's-affected brains.

The plaques consist of dense aggregations of a peptide called beta-amyloid, produced by enzymatic cleavage of a larger protein, Alzheimer's Precursor Protein (APP), expressed in neural tissues.

In a talk to the 28th Lorne Conference on Protein Structure and Function yesterday, Dr David Small of Melbourne University's Department of Pathology described his team's new technique for identifying candidate drugs for treating Alzheimer's disease.

Small and his colleagues suspect that the amyloid plaques may be less harmful than small clusters, or oligomers, consisting of just a few molecules of beta-amyloid - even a two-unit dimer of beta-myloid may be neurotoxic.

Amyloid plaques consisting of millions of beta-amyloid molecules are the endpoint of the polymerisation process -- they grow in situ, are insoluble, and immobile, says Small.

But low molecular weight beta-amyloid oligomers are soluble, and diffusible, says Small.

Hydrogen bonding and hydrophobic forces hold the oligomers together, whereas a new theory of Alzheimer's proposed by Melbourne University researcher Dr Ashley Bush, who is also speaking at Lorne, proposes that amyloid plaques are held together by zinc and copper ions.

Small says recent evidence implicates similar, low molecular-weight oligomers of two other proteins in two other brain disorders, British familial dementia (BFD) and transthyretin amyloidosis (TA).

BFD has symptoms very similar Alzheimer's disease; it involves a protein called ABri. In TA, amyloid plaques consisting of fragments of a hormone-binding protein called transthyretin, accumulate around blood vessels in the brain. The vessels are prone to haemorrhage, causing multiple mini-strokes.

"The possibility that these disorders may involve oligomers of these proteins, rather than the plaques, is one of the more exciting developments of recent years," Small says.

"Even though they involve different monomers, and have very different chemistry, the mechanism is similar -- they all involve folding errors in the parent proteins.

"The fact that the symptoms of British familial dementia closely mimic those of Alzheimer's disease is one of the strongest arguments that these sorts of peptides cause the diseases."

Small and his colleagues at Melbourne and Monash University are using a technique called surface plasmon resonance to investigate how the oligomer fragments bind to the membranes of neurons and glial cells.

They are using the same technique for high-throughput screening of novel therapeutic molecules.

Overseas research has shown that the widely used cholesterol-lowering drugs known as statins, can reduce the risk of Alzheimer's disease.

Small says statins appear to work by lowering the level of cholesterol in cell membranes, which re-orients the heads of the phospholipid molecules to which the beta-amyloid oligomers bind, protecting the cell against toxicity.

This finding, says Small, casts light on why the ApoE4 variant of the cholesterol-transport gene ApoE gene is a key risk factor in Alzheimer's disease.

His team is now establishing a group at Monash that will employ combinatorial chemistry to develop libraries for high-throughput screening, to identify novel compounds that may disrupt beta-amyloid oligomer binding to cell membranes.

-- Graeme O'Neill will continue to report on the latest research from the Lorne Protein Conference all this week