Alzheimer's, Tangles and Tau

Summary: The tangles seen in Alzheimer’s brains are made up of a protein called tau. Tau is involved in Alzheimer’s and other neurodegenerative diseases, but scientists don’t yet understand its role. In the long run, understanding how tau contributes to brain cell death may help researchers develop new Alzheimer’s treatments.

More than a year after Dad died, I’m still trying to understand what caused his dementia and death. His primary diagnosis was cerebral amyloid angiopathy, but “it is likely that the presence of plaques and tangles contributed to his neurologic difficulties,” his autopsy consultation report says.

These plaques and tangles are signs of Alzheimer’s disease. A lot of Alzheimer’s research focuses on plaques and on beta amyloid, the protein that makes up those plaques. Several drugs aimed at preventing the build-up of beta amyloid are being tested. But what about tangles?

The tangles, also found in the brains of people with Pick’s disease and Parkinson’s, are made up of a protein called tau. Tau is found in “normal” brains, and helps stabilize the small tubes that are part of cells’ skeletons. These microtubules transport nutrients through the cells.

Much has been written about the disagreement between scientists who believe beta amyloid causes the brain degeneration seen in Alzheimer’s [“baptists”] and those who believe that tau is the culprit [“tauists”]. But it’s not really an either/or situation - we need to understand the role each protein plays and how they may work together.

Do Tangles Harm Brain Cells?

Were the tangles found in Dad’s brain really harmful to his brain cells? “We’re not certain,” says Dr. Lester Binder, Professor of Cell and Molecular Biology at Northwestern University. “It may be that they’re somewhat protective.”

Lester I Binder, Ph.D.

“Evidence indicates that tangles persist in some neurons for 25 to 35 years,” he says. “Eventually, these cells die, but perhaps not nearly as fast as some other non-tangle bearing neurons.”

In 2005, the results of two studies added to the evidence that tangles might not be causing cell death. Researchers at the University of Minnesota found that when they suppressed tau in mice bred to have human tau, memory improved and cell death stopped, but the tangles continued to form. Another study at the Albert Einstein College of Medicine showed that the presence of tangles in mouse brains didn’t always lead to cell death – instead, it appeared that cell death was caused by brain cells abnormally attempting to enter the cell cycle. The cell cycle is the process in which the chromosomes in a cell are replicated and the cell divides into two new cells. This re-entry into the cell cycle is not normal for adult brain cells, and has previously been linked to neurodegenerative diseases.

Do Changes to Tau Cause Cell Death?

If the tangles themselves don’t cause cell death, then what does? This “whodunit” mystery is more complicated than a game of Clue. In Clue, Mr. Boddy has been murdered, and players must consider six suspects, six possible murder weapons, and nine rooms in which the murder could have been committed. In Alzheimer’s, Mr. Brain Cell is dead, and scientists must consider hundreds of suspects, possible weapons and crime scenes. Those investigating tau are dealing with a lot of uncertainties. Possible tau-related weapons include:

- changes in the form of tau, perhaps when a phosphate gets added to the protein
- changes in the level of tau
- changes in the ratios of types of tau .

There’s uncertainty about who or what causes the changes in tau, too. The list of suspects includes:

- beta amyloid (the protein that makes up Alzheimer’s plaques)
- alpha-synuclein, another protein found in Parkinson’s disease and Alzheimer’s of the Lewy Body type
- impaired glucose metabolism
- a combination of genes plus exposure to toxic metals through diet causing oxidation.

Researchers are also trying to narrow down the location where tau-related cell death might start. Maybe death originates in the microtubules, which could be destabilized by changes in tau. Maybe it was in the cell cycle, but what was Mr. Brain Cell doing there anyway?

In the game of Alzheimer’s, players researching tau and tangles are a long way from winning.

Measuring Tau May Help with Diagnosis

Back in the real world, measuring levels of tau may be useful for diagnosing degenerative brain diseases. Along with levels of beta amyloid, levels of abnormal tau in spinal fluid might predict conversion from mild cognitive impairment to Alzheimer’s or help diagnose Alzheimer’s. Innogenetics, a company based in Belgium, has developed a test to measure tau levels.

Using PET (Positron Emission Tomography) scans and other imaging techniques to map tau in the brain may also help with diagnosis in the future. In late 2006, researchers at UCLA reported that when they injected a substance called FDDNP into 83 people with memory problems, it stuck to both plaques and tangles and could be seen during a PET scan. [If you really want to know, FDDNP stands for fluorescent probe 2-{1-[6-(dimethylamino)-2-naphthyl]ethylidene}malononitrile.] The amount of plaques and tangles shown by FDDNP correlated with the severity of cognitive impairment. The study authors concluded this scan could be used as a tool to differentiate among people with normal memory, those with mild cognitive impairment, and those with Alzheimer’s.

In the future, measuring and mapping tau before and after a treatment may be one indicator of whether that treatment is working.

Potential Alzheimer’s Treatments Targeting Tau

As with beta amyloid, scientists are looking for ways to prevent or treat Alzheimer’s by tinkering with tau. Dr. Binder and his colleagues have shown that an enzyme called puromycin-sensitive aminopeptidase degrades tau in the lab. Scientists at the University of British Columbia are studying how thrombin, a protein involved in blood coagulation, degrades tau, and University of California researchers have found that removing beta amyloid may clear certain forms of tau.

Besides eliminating or reducing tau, other approaches include:

- preventing changes to tau (using lithium or other substances)
- protecting the microtubules in brain cells (using an enzyme called Pin1, the cancer drug Taxol or a compound called NAP, developed by Allon Therapeutics Inc. and now in early clinical trials).

Some scientists think tinkering with beta amyloid could do more harm than good, and tau is no different. I asked Dr. Binder if potential therapies could remove too much tau, since the protein is needed for normal brain function. “This isn’t known as yet,” he says. “Tau knockout mice [bred to have no tau] survive, but it’s not clear how normal they are.”

If removing tau might be dangerous, would it be better to try to regulate the sequence of events leading to changes in tau, or the formation of tangles, rather than remove tau or tangles?

“Perhaps,” says Dr. Binder. “Unfortunately, we are somewhat uninhibited by facts here,” he notes, referring to all the uncertainties about tau. He is sure, however, that investigating tau is worthwhile. “Tau is certainly part of the problem in Alzheimer’s disease and certain inherited frontal lobe dementias,” he says, “and the link between amyloid and tau is currently being explored by both baptists and tauists alike.”

I put Dad’s autopsy report back in the file cabinet for a while. It may be a few more years before I can understand what the tangles were doing in my father’s brain.

Comments

[Gail Rae Hudson]

My favorite part of this post is the "baptist"/"tauist" (read Taoist) reference! What a philosophical poser that is! Not more so, though, than the extraordinary complexity of cognitive impairment. As I was reading your post and enjoying, as well, your analogy to "Clue", I realized that this may not be a game of singular death, either, but several different deaths, all with different circumstances and different murderers. Oh, what gods will we think we are once we have cracked these mysteries!

I have to tell you, Mona, I started reading this post yesterday, I think, or maybe it was the day before. I stopped at a point halfway through when I began to wonder, for a reason I can't, unfortunately, delineate, if there are environmental triggers harbored in the fact that, at the moment, a majority of cognitive impairment problems are appearing in the generation of people "exposed" to WWII. Even those who weren't in the military probably had someone close to them who was. As well, there was a lot of war research, aside from and including atomic research, carried on in this country and others from which the citizens of these countries were not protected, except from the knowledge of it. I'm not one to believe out of hand that we are necessarily and suddenly seeing an "epidemic" outbreak of elderly dementia. It seems more likely to me that the propensity was waiting for the right conditions in order to make its appearance, the most important condition of which would be longevity. But, suppose another important condition is linked to the unusual changing of myriad environments due to WWII (and, later space) research, all of which eventually led to many of the environmental circumstances we are today experiencing which affected everything including, for instance, food production (both agriculture and delivery); the use of increasingly complex chemical solutions in the home for a variety of purposes including the building of devices to make life easier, etc. I know that my mother's and dad's generation embraced all these miracle products of war and space research with extraordinary enthusiasm. My mother so completely embraced canned and frozen food, for instance, that I was completely unfamiliar with the form of many fresh vegetables until I began to live on my own and shop for myself.

I can't help but wonder how many Alzheimer's researchers are following up on environmental factors that might be implicated in the flowering of the latent possibility for cognitive impairment already existing in our bodies.

Just a thought. Not sure how it's connected to anything, but your post initiated this haunting for me.

[k]

Hi, I just found your blog, through googling for cerebral amyloid angiopathy.

The reason I was looking was not to do with Alzheimer's.

Have you heard of CFIDS, or CFS? It stands for Chronic Fatigue (Immune Dysfunction) Syndrome. It is also sometimes called ME (Myalgic Encephalomyelitis).

Dr Baraniuk has been investigating CFIDS, and I just read that apparently his research suggests that maybe "amyloid deposition in the blood vessels of the brain is causing microhemmorhaging".

So I guess you never know when some research on a different illness might eventually throw up something helpful.

BTW, I am in England, and people with Alzheimer’s have trouble getting their drugs here too - see http://news.bbc.co.uk/1/hi/health/4637484.stm