BAP-tists - those convinced that ß-amyloid protein (BAP) is the key to Alzheimer's disease (AD) - have long outnumbered TAU-ists - or those who believe the culprit is tau. ß-amyloid protein is, after all, the major component of amyloid plaques in the brains of AD patients. And the BAP-tists can point to a handful of mutations and other data to support their belief.
But another obvious, abnormal feature characterizes AD brains: neurofibrillary tangles consisting mostly of tau, an abnormal protein form. Tau normally stabilizes microtubules that provide a framework for moving nutrients in cells. In many dementias tangles of unnaturally modified tau fill cell bodies, while amyloid plaques seem limited mainly to patients with AD and to the elderly. Thus a small but dedicated minority considers tau to be a prime suspect in cell death associated with dementias.
“There has been a long debate about what the tangles mean. Are they the end products of cells dying, or are they active participants in cell death?“ asks Gerald Shellenberg, associate director for research at the Geriatric Research Education Clinical Center, Veterans Affairs Medical Center, in Seattle.
Now TAU-ists have new information to support their belief. Three research groups have published studies identifying mutations in the tau gene in families susceptible to non-AD dementias. The findings hold implications for the 3 percent to 10 percent of dementia patients suffering from frontotemporal dementia (FD), as well as for those with AD.
The new results do not rule out BAP as a prime factor in AD, but they do establish another important cause of neuronal death in dementias.
The first report, “Tau is a candidate gene for chromosome 17 frontotemporal dementia,“ appears in the June issue of the Annals of Neurology. Shellenberg and his co-authors describe a missense mutation in a family with a recently defined disease called frontotemporal dementia with parkinsonism, chromosome 17 type (FTDP-17), a familial form of FD. Frontotemporal dementia most often occurs in families, sporadically and rarely, as an inherited autosomal-dominant trait.
The researchers describe a point mutation in one of two FTDP-17 families and, in a note, report a second family with a different point mutation. Described in detail, this mutation, they believe, causes dementia because it is highly conserved, co-segregates with the disease in the affected family and is absent in control subjects.
“We have found three or four more mutations since the paper was submitted,“ Shellenberg told BioWorld International.
Other Mutations Described
Still more mutations will be described in the June 18 issue of Nature, in a paper titled “Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17.“ Along with 50 colleagues, Michael Hutton, assistant professor at the Mayo Clinic in Jacksonville, Fla., studied families with inherited FTDP-17 from five countries. Besides the missense mutation detected by Shellenberg et al., the Nature paper describes two other missense mutations, plus three mutations in a region of the gene known as exon 10. (Exons are stretches of nucleotides that encode amino acids that end up in the final gene product. Introns are intervening sequences normally cut from RNA copies before the protein product is completed.)
The mutations Hutton and coworkers found in exon 10 could all produce tau molecules that contain repeats of regions that normally regulate tau binding to microtubules. Tau molecules with these abnormalities are seen in several families with FTDP-17.
Finding mutations in introns is a bit unusual. Geneticists usually start looking at exons, not introns, for disease genes.
“It is just because these mutations are so unusual, and they occur in the introns, that they were missed over and over again,“ Hutton explained. “Also, because of the nature of the mutations, they are rather hard to detect by sequencing.“
A Tau Gene Mutation
Another report, in the Proceedings of the National Academy of Sciences, “Mutation in the tau gene in familial multiple system tauopathy with presenile dementia,“ is scheduled to appear June 23. Maria Grazia Spillantini - a lecturer at the Medical Research Council Centre for Brain Repair and at the department of neurology in the University of Cambridge, in the U.K. - and her colleagues studied a family with a form of FTDP-17 called multiple system tauopathy with presenile dementia. They found a guanine-to-adenine mutation in the intron following exon 10 of the tau gene. They also report an increase in the number of tau molecules with four microtubule binding repeats compared to those with three such repeats. This change in ratio of different versions of tau evidently leads to the formation of abnormal tau filaments in neurons, according to the authors.
“To many people it now appears that tau is relevant because if you have a malfunction or aggregation of tau, you have neuronal death and clinical symptoms,“ Spillantini said.
The other authors agree.
“What these mutations show is that if you alter the structure of tau, you kill neurons,“ Shellenberg said.
Abnormal tau molecules that do not bind to microtubules may be subject to the actions of enzymes that add phosphate groups to them. Eventually entire neurons become filled with tangles of hyperphosphorylated tau.
Still unclear is what kills neurons: tau's inability to perform its function as a stabilizer of microtubules or the tau aggregates. This is the question on which Spillantini and her colleagues are focusing.
Hutton's group is now attempting to determine the prevalence in the general population of the tau mutations and to understand the mechanisms by which the intron mutations affect the production of abnormal tau. Several groups are trying to create animal models that will enable them to test the ability of drugs to prevent aggregation and neuronal death.
“Even if tau is not causing the primary lesion in Alzheimer's disease, it is involved in the pathway to cell death somehow and at some point. And that in itself is a really major find,“ Hutton said. *