By David N. Leff

Dementia pugilistica is what neurologists call punch-drunk. It¿s what boxers suffer from repeated blows to the head. The symptoms of this chronic brain condition include slurred speech, mental deterioration and a characteristic broad-based gait.

When such a damaged fistic fighter dies ¿ but not before ¿ neuropathologists can confirm the diagnosis of dementia pugilistica by detecting hallmark clumps of a protein called tau in the traumatized cerebral neurons. These neurofibrillary tangles are also found in the moribund neurons of Alzheimer¿s disease (AD) post-mortem brains.

¿The tau gene resides on human chromosome 17,¿ observed clinical neuropathologist Mel Feany. ¿The function of the protein it expresses in the human brain,¿ she added, ¿is to bind to protein arrays called microtubules. These are long stretches of tau proteins that help feed important molecules from the neuronal cell body down the axon. Tau normally binds to those train tracks, and helps stabilize them.

¿Mutations in tau,¿ Feany continued, ¿which are insoluble, make it bind less readily to microtubules, and aggregate more readily. Those defective taus now adhere to one another and form abnormal structures, which eventually accumulate in neurofibrillary tangles.

¿What¿s extremely significant about the chromosome 17 localization,¿ she pointed out,¿ is that there are rare familial mental diseases known as FTDP-17 ¿ frontotemporal dementias and parkinsonism linked to chromosome 17. The tau gene is abnormal in those families. Like AD, their brain cells contain the tau fibrillary tangles. This says,¿ Feany went on, ¿that just mutating the tau gene can cause neurodegeneration.

¿As is the case for AD, there are no therapies for these familial dementias ¿ these tauopathies,¿¿ Feany said. ¿They¿re much more uncommon ¿ 1/100th less frequent than AD. Two of the major features that would distinguish these diseases from AD are emotional abnormalities. AD patients are very forgetful, but emotionally they¿re pretty well intact. They react normally, and for the most part don¿t display bizarre behaviors.¿

Tangle-Bearing Rare Dementias Act Weirdly

¿FTDP-17 patients can manifest unusual, bizarre actions,¿ Feany continued. ¿They may be hypersexual, antisocial, and often have motor symptoms. Patients with AD don¿t have trouble walking around, but some of the frontotemporal type don¿t walk as quickly, and might have tremors and stiffness. Again like AD, at the present time they can be diagnosed only by postmortem analysis.

¿The important thing about having this fruit fly model of AD and FTDP-17,¿ she observed, ¿is that not only might we find therapeutic targets. Those same molecules potentially are going to be used as markers before death to diagnose these diseases.¿

Feany, who heads a neuropathology laboratory at Brigham & Women¿s Hospital, in Boston, is senior author of an article in today¿s Science, dated June 15, 2001. Its title: ¿Tauopathy in Drosophila: Neurodegeneration without neurofibrillary tangles.¿

¿The most important point of our paper,¿ she told BioWorld Today, ¿is that we now have a genetic model that will allow us for the first time to use the sophisticated tools of genetics to understand how tau actually kills nerve cells ¿ something we know very little about.¿

Among the things she does know about is that ¿a mouse model of tau can¿t easily be used to identify new genes and proteins involved in the pathogenesis of AD and other tauopathy disorders. Genetic analysis in mice is much slower and more expensive than the same analysis in fruit flies. We¿re able with genetics to identify a large number of genes that are very important in mediating tau degeneration.

¿We can easily clone the flies now, but we usually don¿t have to because Drosophila¿s whole genome has been sequenced. We can easily identify the proteins these genes encode. We can¿t find new genes and proteins easily in mice.

¿Fruit flies are really much better drug-screening tools than mice,¿ Feany pointed out, ¿because they¿re very small, they¿re cheap, they don¿t live very long, and they eat anything. So you can stick candidate compounds into flies, and they¿ll eat ¿em up. Their lives are short ¿ two months on average ¿ so you have a defined endpoint. The pathologies we described were evidenced between 10 and 30 days, so we could look at them in a very short period of time.

¿We were able to show,¿ she observed, ¿that certain brain cells, the cholinergic neurons that use the acetylcholine neurotransmitter as a messenger molecule, were more susceptible than other kinds of neurons to the action of tau. And cholinergic neurons are some of the first brain cells to die in AD. As a matter of fact, the only drug therapies that are available right now are aimed at increasing the action of acetylcholine in the Alzheimer¿s brain.¿

The neurofibrillary tangles inside AD neurons and the amyloid-beta perpetrators of senile neuritic plaques surrounding those dying brain cells have long been construed as the yin and yang of AD etiology. Until lately, plaque researchers won more grant funding than tangles investigators.

¿That¿s mostly resolved,¿ Feany said. ¿There¿s clearly no question that tau can cause dementia. If you look carefully at the brains of people with AD, the tau or tangle pathology is much more highly correlated than amyloid plaques with loss of memory. So I think almost everybody in the field now feels happy to say that amyloid triggers the plaque process that then implicates tau, and probably cell death is mediated, at least to some degree, through tau.¿

Are Tangles Chicken Or Egg Of AD?

But another question hangs fire: Are those tangles the cause of AD, or its consequence?

¿That¿s a question I think I can answer,¿ Feany proposed. ¿In our fly model, tangles do not cause cell death ¿ period. We were able to show this because I looked into the AD cells by electron microscopy, and saw more than 500 of them dying out. There were no tangles. So tangles in our system do not kill cells.

¿But we have to be cautious extrapolating our results from Drosophila melanogaster to Homo sapiens,¿ she demurred. ¿I feel that the fruit fly is a good model for the human disease, so I think we can suggest that tangles don¿t kill neurons. But of course flies are not people. So we can¿t say definitively that in humans, tangles don¿t cause death.¿

No Comments