The Tangled Neuron

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.

Change of Shift

The new Change of Shift is up at Emergiblog - it will give you a new appreciation of nurses!

Grand Rounds 3.18...

...is up at Signout. The host, Dr. Signout, has put together a nice collection of posts on the intersection (or lack thereof) between scientific evidence and healthcare.

SORL1: New Alzheimer's Gene

Summary: A new study shows variations in a gene called SORL1 are associated with an increased rate of late onset Alzheimer’s. The effect of this gene on your risk of developing the disease is probably modest, and researchers don’t know which variations of the gene could increase that risk. The results of this study will not lead to a simple genetic test for increased risk of Alzheimer’s, at least not anytime soon. But the discovery, along with related research, may generate new ideas for Alzheimer’s treatments.

I’ve been taking a break from blogging about Alzheimer’s and dementia. But when I picked up the newspaper from our driveway Monday morning, the top headline screamed “Gene linked to Alzheimer’s.” “More than 40 scientists worldwide find an inherited flaw that can lead to the disease,” the subtitle said.

I’m tired of headlines announcing Alzheimer’s breakthroughs, but decided to check it out anyway.

The headline referred to a new study that shows variations in a gene called SORL1 are associated with an increased rate of late onset Alzheimer’s. Results of the study, conducted by researchers from fourteen universities and institutes, were published online in the February edition of Nature Genetics.

Despite my skepticism about the headline, this study is intriguing. But it doesn’t mean a simple genetic test can tell you if you’re at increased risk of developing Alzheimer’s, at least not anytime soon.

To understand why the study is important, you have to look at related research results published in the last few years.

SORL1 in the Alzheimer’s Brain

Some of the early clues that SORL1 might be involved in Alzheimer’s came from physiological, rather than genetic, studies. First, scientists found that the level of the protein SORL1 was lower in the brains of people who had late onset Alzheimer’s than it was in “normal” brains.

How is a protein related to genes? The information stored in our genes is used to make proteins. Variations in genes (either inherited or that happen during a person’s lifetime) change how proteins are made. The theory is that variations in the SORL1 gene change how the corresponding protein (also called SORL1) is made, perhaps by regulating levels of the protein.

With the new study, there is now evidence that SORL1 may contribute to the risk of Alzheimer’s on both a physiological and a genetic level.

SORL1 Affects Levels of Beta Amyloid

Dr. James Lah is Assistant Professor of Neurology at Emory University, and co-author of the study linking SORL1 protein levels to Alzheimer's. Last year, he and his colleagues found that decreasing levels of the SORL1 protein increases the amount of beta amyloid near cells in lab tests. Beta amyloid is the sticky protein that makes up the plaques found in the brains of Alzheimer’s patients.

James J. Lah, M.D., Ph.D.

This finding is exciting for researchers who think beta amyloid causes Alzheimer’s, and are working on treatments targeting that protein.

“The available data support an important role for LR11 [SORL1] in AD pathogenesis and identify this receptor as a potential novel therapeutic target for treatment of late-onset sporadic AD,” Dr. Lah and his colleagues wrote in their paper published last year in the Journal of Neuroscience.

SORL1 Is a Receptor for APOE

In addition to the link between SORL1 and beta amyloid, there’s a connection between SORL1 and the APOE gene already known to influence the risk of developing Alzheimer’s. The protein SORL1 is a receptor, which means when a specific molecule is nearby, SORL1 binds itself to that molecule, and then causes a reaction within a cell. The specific molecule it binds to is APOE.

APOE is a kind of protein involved in processing cholesterol and other fats. A variation in the corresponding APOE gene, APOE4, has been linked to Alzheimer’s disease. Given this link, APOE variations change the effect of SORL1 variations on Alzheimer’s risk, or vice versa?

“When we began studying LR11/SorLA our first efforts were directed at finding a relationship between it and APOE,” says Dr. Lah. “Their interactions have been surprisingly elusive. However, in my opinion, it is difficult to believe the functional links are merely coincidental. I expect that further work will define the nature of their interactions at both genetic and physiological levels. With the added attention that will follow the Nature Genetics paper, I expect this will come out pretty quickly.”

Intriguing, But More Research Needed

So, why won’t these discoveries lead to a simple genetic test for increased Alzheimer’s risk anytime soon?

While it’s too early to tell how much the SORL1 gene affects the chances of developing the disease, the co-authors of the new paper write that they believe the effect will be “modest.” There are several reasons for this.

First, SORL1 and APOE are just two of many genes suspected to affect the risk of developing Alzheimer’s. In an article published in the January issue of Nature Genetics, researchers at Massachusetts General listed 13 other “potential Alzheimer disease susceptibility genes.”

Second, scientists involved in the new genetic study couldn’t identify which variations of the SORL1 gene might increase the risk of Alzheimer’s. “In sharp contrast to APOE (where APOE e4 is associated with Alzheimer disease in most data sets), no single SORL1 SNP [common variation] or haplotype is associated with increased risk for Alzheimer disease in all six data sets,” they wrote in the article published this week.

Third, the study didn’t show an association between variations of the gene and increased rates of Alzheimer’s in two of the sample populations studied: Caucasians from the MIRAGE (Multi-Institutional Research in Alzheimer's Genetic Epidemiology) study and another set from the Mayo Clinic in Rochester.

This does not necessarily mean that SORL1 is not a risk factor for the populations the people studied represent. “One possible explanation for lack of association in these data sets is genetic heterogeneity,” says Dr. Lindsay Farrer, one of the study’s authors and Chief of the Genetics Program and Professor of Medicine, Neurology, Genetics and Genomics, Epidemiology, and Biostatistics at Boston University School of Medicine. The problem is that multiple variations in the SORL1 gene may contribute to increased risk. “Specifically, in these samples representing perhaps many ancestral European populations there is no one SORL1 SNP variant or haplotype sufficiently enriched to show an association,” he says.

Dr. Farrer also says perhaps the groups in which no association was found just weren’t big enough, especially given the conservative statistical approach used in this study. It may also be that other causes of Alzheimer’s (genetic or not) were somehow over-represented in these groups.

Despite these uncertainties, the results from this analysis of the genetic material, family relationships and medical histories of over 6000 study participants “suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease,” wrote Dr. Farrer and his colleagues.

The scientists supplemented their genetic findings with research on the physiological level by testing for levels of SORL1 in the blood of participants. Those diagnosed with Alzheimer’s had blood levels of SORL1 less than half that of non-Alzheimer’s participants. But this finding had its own uncertainties: only about 14 percent of that difference was accounted for by SORL1 variations.

They also showed in lab tests that decreasing SORL1 in cells increased the production of beta amyloid. This confirmed the earlier research described above, and the results of these new tests will add detail to the hypothesis about the mechanism by which SORL1 may affect beta amyloid.

Something Dr. Lah said helps clarify the connection between the genetic and physiological research for me. “I believe we are entering a new period in which we will be identifying genetic influences on the common late-onset forms of Alzheimer's which individually modify risk more modestly than the very, very potent effects associated with APOE,” he says. “However, these new findings are likely to shed light on physiological pathways that will lead to development of new and more effective treatments for Alzheimer's disease.”

More study on both genetic and physiological levels is needed. “My co-investigators and I encourage other researchers to evaluate association with SORL1 in other datasets,” says Dr. Farrer. “We predict that many, perhaps most, but not all data sets of reasonably large sample size will demonstrate association with one or more SNPs [common variations]. While confirmation is certainly important, in light of our results in which we could not identify any of the SNPs showing association with AD to be functionally or biologically relevant, more intensive interrogation of other variants in this gene is warranted.”

Dr. Lah is a bit less cautious. “I am admittedly biased,” he says, “but I believe that the SORL1 genetic association will hold up, and that LR11/SorLA in Alzheimer's disease will emerge as an important aspect of the disease.”

Reading through the study again, I realize it’s a good example of why there’s often a disconnect between optimistic Alzheimer’s headlines (which set our expectations too high) and the realities of research. The study is big, hard for a non-scientist to understand, and full of twists and turns. Nothing is simple in Alzheimer’s research. But that isn’t the researchers’ fault. We need to have realistic expectations, and support those who are willing to work in this difficult area. I guess I’ll get back to blogging.