By David N. Leff

Day trading on the stock market is kids¿ stuff compared with betting on which comes first, plaques or tangles, as the root cause of Alzheimer¿s disease (AD).

Two pathological roots ¿ amyloid plaques and neurofibrillary tangles ¿ contend for the title of AD¿s primary etiology. Like stock quotations, these competing hallmarks reflect not just prestige but take-home earning prospects.

¿We are seeing evidence of interactions between the two pathologies,¿ observed neuroscientist Michael Hutton. ¿We see a dramatic enhancement of the neurofibrillary tangle pathology in the limbic areas of our mouse brains, around the cerebral cortex and the amygdala. These are the earliest areas affected in AD.

¿This clearly provides evidence,¿ he continued, ¿that the amyloid plaque pathology is influencing distribution of the neurofibrillary tangles [NFT] pathology. That¿s important for two reasons: First, it provides very good evidence for some kind of interaction between the amyloid pathology in AD and the tau-driven NFT pathology. That¿s a question that¿s been argued and debated about for 10 or 15 years. And the second important point is that what we can now do is use our transgenic mouse and major variants of it ¿ we¿re still trying to improve the model ¿ to test therapeutic compounds that are aimed at reducing the amyloid pathology in the animals, to see if they¿re also able to reduce this enhanced NFT.¿

Hutton, an associate professor of neuroscience at the Mayo Clinic¿s branch in Jacksonville, Fla., is corresponding author of a paper in the current issue of Science, dated Aug. 24, 2001. Its title: ¿Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP.¿

¿What we did,¿ Hutton told BioWorld Today, ¿was take two individual strains of mice that separately model AD. They develop amyloid pathology, produced by expressing a mutant form of APP. That¿s the amyloid precursor protein, a fragment of which cleaves off as the amyloid-beta peptide that makes neurotoxic amyloid plaques surrounding the AD neurons.¿

Double-Transgene Mice Mimic AD Hallmarks

¿One starter mouse strain,¿ Hutton recounted, ¿developed amyloid pathologies very robustly for about 10 months of age, but the second animal line didn¿t show any neurofibrillary tangles ¿ the other toxic structure in degenerating AD neurons. We crossed these two lines together. They developed NFTs by expressing a mutant version of the tau protein, which is the major component of the tangles. Most mice developed NFT predominantly in the limbic system and the olfactory cortex, which are affected in AD.

¿When we crossed the two strains,¿ Hutton went on, ¿obviously their progeny had plaques and tangles. To raise this bitransgenic animal model,¿ he related, ¿we took animals that developed amyloid plaques and crossed them with mice that developed neurofibrillary tangles. This strain we raised ourselves. The parental strain, which has the tangles on the plaques, when we put the two together, we see the limbic pathology. The key point is that the tangles on the NFT mice showed dramatic enhancement in those limbic areas.

¿We started with a tau mouse line that develops NFTs,¿ Hutton recalled, ¿and crossed them with mice we had obtained from the Mayo Clinic. This line carries mutations seen in early AD patients. Both mice originally developed amyloid disorders from around 10 months of age. They¿ve become the most widely used models for amyloid pathology. Since 1996, Mayo distributes them to academics and industrial companies.¿

Hutton continued his account: ¿We took both our amyloid mice and our tau mice, did a simple male-female cross, and ended up with one in four ¿ the Mendelian ratio ¿ of the double transgenic progeny. We aged them as long as we possibly could and looked at the phenotype of these mice at three, six and 10 months of age. The aim of our in vivo experiment was to see if indeed the extracellular senile amyloid plaques and the intracellular tau tangle features of AD influenced each other in the disease process.¿

Interactions Shown But Debate Goes On

¿Our mice carrying two mutant transgenes directly paralleled what we see in AD,¿ Hutton said. ¿It¿s good evidence that this amyloid/tau interaction is occurring. Yet it still leaves enough room for argument that the interaction we¿re observing isn¿t an exact parallel of the clinical situation one sees in the disease. But it¿s getting harder and harder to argue against it, that¿s for sure.¿

Asked whether the opposing viewpoints of these two groups are reflected in the putative therapies they espouse, Hutton responded: ¿Very much so. And I think that¿s good. Certainly the amyloid and tau camps are coming much closer together. That¿s my impression. The general idea that both molecules are probably important, but that the AD plaque lesion is initiated either by amyloid-beta production or APP dysfunction, is becoming much more widely held.

¿And equally the belief that tau is important at some molecular level is being widely held as well. But there¿s no question: The people who work on tau are looking at therapies based on the tau protein. And the people who work for APP and amyloid aim at treatments based on amyloid protein. I think the evidence is pretty strong,¿ Hutton observed, ¿that they¿re both potential drug targets. So clearly, we want to see compounds developed for multiple compounds. Most of the work is currently focused on knocking down amyloid-beta, or clearing amyloid, and I think that¿s reasonable, given that most people believe it¿s the primary plaque agent. But we have no idea if those therapies will work in the clinic, so I think it¿s really crucial that groups look at other potential targets beyond simply A-beta.¿

Back to back with the Mayo Clinic¿s article in Science is a separate but strikingly similar paper by neuroscientists at the University of Zurich, Switzerland, titled: ¿Formation of neurofibrillary tangles in P301L tau transgenic mice induced by Ab42 fibrils.¿ Its senior author is neuroscientist Roger Nitsch.

¿Our results are very similar,¿ Hutton pointed out. ¿Whereas we chose this amyloid-beta/tau cross, Roger went for A-beta injection into the mouse brain. Both our systems have advantages and disadvantages, and they complement each other very well.¿

Capping that climax, a one-page editorial in Science, titled ¿Tauists and baptists united ¿ well almost!¿ cautioned: ¿It would be wise for future AD therapies to combine targeting of amyloid-[beta] deposits with strategies for eliminating tau tangles.¿