Cross-linked beta-amyloid implicated in Alzheimers

Cross-linked oligomers of beta-amyloid (AB) may be the primary neurotoxic agent in Alzheimer's disease according to Rob Moir, an expatriate Australian researcher in Rudolph Tanzi's Genetics and Aging Research Unit at Massachusetts General Hospital and Harvard University.

Moir presented details of his research into the cross-linked beta-amyloid protein species (CLAPS) to delegates at last week's ComBio2004 meeting in Perth.

"A lot of people are looking at clearance of monomeric AB, but a lot of it is in the form of dimers, trimers and other oligomers," he said.

CLAPS are formed when AB is oxidised in the presence of copper, suggesting that the troublesome protein fragment plays an important role in protecting the brain from oxygen free radical species, Moir said.

The clearance of AB by lipoprotein receptor-related protein (LRP) involves the formation of complexes between AB and chaperones including alpha-2-macroglobulin (a2M) and apolipoprotein E (ApoE). But these two proteins have a low affinity for CLAPS, he said.

Moir's research has also shown that levels of serum auto-antibodies against CLAPS were significantly reduced in patients with Alzheimer's disease, compared to non-demented controls -- a surprising result, he said, as levels of autoantibodies to AB have not been definitively linked to disease.

In addition, the level of immunoreactivity to CLAPS correlated well with the age of onset of Alzheimer's disease.

It adds up to a tantalising hint that anti-CLAPS antibodies may provide some protection against the onset of Alzheimer's disease, Moir said. Lower levels of antibodies might results in less clearance of the complexes from the brain, hence allowing the disease to develop.

Moir said that while the research was still at an early stage it opened new avenues for developing diagnostic methods and therapeutics.