In addition to AD, tau pathology is associated with over 20 different diseases, or tauopathies, making tau-based treatments a potential panacea for many neurological disorders. Niemann-Pick’s, which is just one of those diseases, is caused by a mutation in either NPC1 or NPC2, proteins involved in lipid trafficking and cholesterol homeostasis (see ARF related news story). In humans, Niemann-Pick’s (not to be confused with Pick's disease) causes progressive neurodegeneration and is associated with NFTs. In NPC1-deficient mouse models of the disease there are no NFTs, but tau kinases are activated and hyperphosphorylation of tau is rampant. Elrick suggested that the mice die before tangles get a chance to form.

To investigate the role of tau in Niemann-Pick’s, Elrick and colleagues crossed NPC1-null mice with tau knockouts. Surprisingly, he showed that the NPC1/tau double null mice have an enhanced phenotype and die significantly earlier than the NPC1 knockout animals, suggesting that tau has a protective role. To figure out what that might be, Elrick looked at autophagy, which is known to be partially elevated in Niemann-Pick’s—LC3II, a marker of the autophagic process is upregulated, as are autophagosomes, but flux through the pathway is reduced by about 75 percent, indicating that processing through the pathway is not robust.

In the tau-deficient mice, Elrick found that LC3II levels were normal. He also showed that induction and flux through the autophagic pathway is reduced in NPC1/tau-deficient human fibroblasts. Since protein degradation through the autophagy pathway depends on microtubule-associated movement, Elrick concluded that tau hyperphosphorylation negatively impacts autophagy and so contributes to disease pathology.

One way to prevent that tau phosphorylation is to block the kinases that are involved. Duff showed that one potential target, the kinase Cdk5, is, in fact, less than ideal. Cdk5, and its co-activator p25 have been implicated in AD pathology (see ARF related news story), and there are conflicting reports that p25 is elevated in AD patient brains, but Duff pointed out that blocking this kinase actually results in more tau phosphorylation because another tau kinase, glycogen synthase kinase 3β (GSK3β), is activated. Blocking GSK3β—with lithium chloride, for example—might be a better approach, suggested Duff (see Noble et al., 2005). But she cautioned that any tau therapy might have to be given early because once tangles form, they can continue to accumulate even after tau is suppressed (see ARF related news story). This could be one reason why AD clinical trials are failing, suggested Duff (see ARF related Keystone story on propagation of tau pathology from cell to cell).

One way to deal with those later consequences of tau pathology would be to find compounds that disaggregate tau fibrils. Duff has developed organotypic cell cultures using tau transgenic mice to screen for such compounds. The tissue can be taken from 10-day-old animals and cultured for months, Duff said. Taking tissue from both sides of the brain allows for both control and test samples. With this method, Duff and colleagues have discovered C11, a cyanine dye derivative, that reduces fibrils. Duff showed that at low doses, C11 reduces the length and number of tau filaments formed in cultures, as seen in the electron microscopes following sarkosyl extraction of the tissue. The low dose does not appear to have any detrimental effect on the cells. High doses of C11 seem to have the opposite effect, however, promoting tau aggregation. Duff plans to further study C11 and use the organotypic culture method to find better tau disaggregating compounds.—Tom Fagan.