15 May 2002 16:58 GMT

by Apoorva Mandavilli, BioMedNet News

Two new papers proposing different therapeutic strategies for Alzheimer's disease (AD) serve only to expose the confusion and "spin-doctoring" that have resulted from controversial developments in the field, according to one expert. The divergent papers, due to be published tomorrow, "show what a state the field is in," Mark Smith, associate professor of pathology at Case Western Reserve University, told BioMedNet News.

Trials for the vaccination approach to AD came to an abrupt halt earlier this year after some patients developed severe inflammation. Failure of the much-hyped approach, based on immunization against the beta-amyloid peptide, further fuelled the decades-long debate on the role of amyloid in AD.

The vaccination approach failed "at least partly because it was badly planned and premature," said Mark Pepys, professor and head of medicine at the Royal Free and University College Medical School in London.

In contrast, says Pepys, his own approach to remove amyloid deposits has been finessed over 20 years, and the results published only when "robust and well-established."

In this week's Nature, Pepys and his colleagues describe a "completely new drug, a completely novel mechanism" for treating amyloidoses, a characteristic feature in Alzheimer's disease, type-2 diabetes, and other disorders.

Using high-throughput screening, the researchers identified a compound that removes Serum amyloid P (SAP), a molecular chaperone that is thought to stabilize amyloid deposits by protecting them from being digested.

They propose that their drug can remove SAP from amyloid deposits in the AD brain, and destabilize the fibrils. They are set to begin clinical trials with AD patients in the UK next month.

Smith is concerned, however.

After years of arguing that the large amyloid fibrils are the toxic species in AD, prominent researchers are now "spin-doctoring" the hypothesis that it is small oligomers of amyloid, rather than the fibrils, that are toxic, says Smith. Harvard University's Dennis Selkoe last month published a paper in Nature supporting the new model.

If that's accurate, argues Smith, removing SAP could release the toxic oligomers from the larger fibrils, and "actually make [the disease] worse."

If amyloid is a component of the toxic species, "and that's a big 'if'," Smith said, researchers must first resolve the controversy over whether it is amyloid oligomers or fibrils that are toxic. "I'm incredulous that we could speculate on therapeutic strategies when we don't know what the toxic species is."

It is "naïve" not to address the controversy over the identity of the toxic species, agrees Joel Buxbaum, professor of molecular and experimental medicine at the Scripps Research Institute, and a self-professed friend of Pepys.

There are also "many investigators who believe that fibrils reflect a protective mechanism," Buxbaum added. "I don't think this is going to do what [Pepys] thinks it will do."

A second paper, to be published in this week's Neuron, further highlights the confusion that prevails in AD research, says Smith.

Investigating the "wingless" signaling pathway in the fruitfly, researchers at the University of California in Los Angeles have stumbled onto a novel model to study the role of the protein tau in AD-related neurodegeneration.

Several researchers believe it is abnormal phosphorylation of Tau, rather than any aggregate of beta-amyloid, that causes AD. The fly model offers a "genetically sensitized" screen to search for novel therapeutic targets in AD, the UCLA scientists suggest.

Scientists have been working on beta-amyloid since 1984, points out Smith, but still don't know whether it is toxic. "It's a pretty poor showing that after 20 years we don't know whether something is good or bad," he said. "How can we then reasonably devise a therpauetic strategy?"

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See also:
Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal ...
Walsh DM, Klyubin I, Fadeeva JV, et al.
Nature, 2002 Apr 416:535-9

Serum amyloid P component prevents proteolysis of the amyloid fibrils of Alzheimer disease ...
Tennent GA, Lovat LB, Pepys MB
Proc Natl Acad Sci U S A, 1995 May 92:4299-303

Inhibition of Alzheimer beta-peptide fibril formation by serum amyloid P component
Janciauskiene S, García de Frutos P, Carlemalm E, et al.
J Biol Chem, 1995 Nov 270:26041-4

The cause of neuronal degeneration in Alzheimer's disease
James C. Vickers, Tracey C. Dickson, Paul A. Adlard, et al.
Progress in Neurobiology, 2000, 60:2:139-165

Preclinical and clinical challenges in the development of disease-modifying therapies ...
[Therapeutic focus]
Carol A. Scorer
Drug Discovery Today, 2001, 6:23:1207-1219

Targeting small A-beta oligomers: The solution to an Alzheimer's disease conundrum?
[Review]
William L. Klein, Grant A. Krafft, Caleb E. Finch
Trends in Neurosciences, 2001, 24:4:219-224

Alzheimer's disease - do tauists and baptists finally shake hands?
Opinion]
Amritpal Mudher, Simon Lovestone
Trends in Neurosciences, 2002, 25:1:22-26
 

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