Elan Corp plc and Wyeth generated much excitement with yesterday's announcement of their plan to begin Phase III testing of bapineuzumab (AAB-001) for mild to moderate Alzheimer's disease later this year. (See BioWorld Today, May 22, 2007.)

Bapineuzumab targets amyloid beta, as do the majority of therapeutic agents that currently are in clinical development. Clumps of misfolded amyloid beta protein, known as amyloid plaques, are one of the cellular hallmarks of Alzheimer's disease, making them natural targets. Recent studies suggested a new way to manipulate amyloid beta levels, as well as an avenue for taking on Alzheimer's independently of amyloid beta.

In a paper to be published in the May 29, 2007 issue of the Proceedings of the National Academy of Sciences, and now available online, scientists link alterations in the wnt signaling pathway to the risk of developing late-onset Alzheimer's disease.

A previous genome-wide association study had shown a region related to Alzheimer's risk on chromosome 12. In the new paper, the researchers identified a specific single-nucleotide polymorphism that led to an amino acid substitution in a receptor for the protein wnt, and increased the risk of developing Alzheimer's in its carriers. On a cellular level, the altered wnt receptor was less active than its counterparts.

First author Giancarlo De Ferrari Valentini told BioWorld Today that one way Alzheimer's disease could be understood is "as a loss of function of the wnt signaling cascade. That would mean that the pathological hallmarks of AD . . . would be related to the loss of proper function of the wnt signaling cascade." Senior author Randall Moon added that the PNAS data showed that "patients may benefit from a weak activation of the wnt/beta-catenin pathway."

Wnt is an important developmental signaling molecule, and has been linked to several other conditions besides Alzheimer's. In fact, for Moon, the PNAS paper comes a mere three days after a paper in the May 19, 2007 issue of Science demonstrating that some forms of kidney cancer may result from abnormalities in the wnt signaling pathway.

Asked whether wnt's involvement in other diseases, especially in cancer, could prove a problem for targeting the molecule in Alzheimer's disease, Moon told BioWorld Today that targeting the wnt pathway sufficiently far upstream would make all the difference. The wnt pathway regulates the protein beta catenin, which regulates the steady-state level of the protein beta-catenin. Beta-catenin usually is degraded rapidly; only if the wnt pathway is activated does it accumulate.

Among its many talents, beta-catenin contributes to bone formation, and epidemiological data showed that people whose wnt pathway is unusually active have high bone density without having a higher cancer risk than normal. Moon said that shows "beyond the shadow of a doubt, that you can activate the wnt signaling pathway without causing cancer," as long as it happens upstream of beta-catenin degradation.

Because the wnt pathway influences the processing of amyloid beta, any therapeutics aimed at wnt or beta-catenin most likely would have their effects via altering amyloid beta processing. In another recent paper, published in the May 4, 2007 issue of Science, researchers showed that another protein also could be a promising target. By reducing levels of the protein tau, they prevented the neurological deficits related to Alzheimer's disease.

In addition to amyloid plaques, tau protein aggregates - technically, neurofibrillary tangles - are a second hallmark of Alzheimer's disease. But therapeutically, tau has received less attention than A-beta. One main reason is that it has been hard to target mutant tau protein specifically.

The Science paper gets around that problem in the simplest of ways - by ignoring it. The researchers lowered overall tau levels with no regard to whether their tau was mutant or not.

The researchers knocked out tau in a transgenic mouse model of Alzheimer's that is engineered to express high levels of human amyloid precursor protein. Knocking out tau did not alter the high levels of amyloid-beta in the APP transgenics, but it did prevent the cognitive impairments that usually beset them.

The exact mechanism by which tau reduction could protect the brain suggested that the findings may not be limited to Alzheimer's: tau reduction protects brain cells against overstimulation. Such overstimulation contributes to a variety of neurological diseases; in their paper, the scientists showed that mice with reduced levels of tau were also resistant against epileptic seizures.