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NOVA ScienceNOW

Of Mice and Memory: Expert Q&A

  • Posted 07.01.08
  • NOVA scienceNOW

On July 1, 2008, Li-Huei Tsai answered questions about Alzheimer's disease and her research into the recovery of memories.

Li-Huei Tsai

Li-Huei Tsai

Li-Huei Tsai is the Picower Professor of Neuroscience in the Department of Brain and Cognitive Sciences at MIT and a Howard Hughes Medical Institute Investigator. Full Bio

Photo credit: Courtesy Betsy Cullen Photography

Li-Huei Tsai

Li-Huei Tsai is the Picower Professor of Neuroscience in the Department of Brain and Cognitive Sciences at MIT and a Howard Hughes Medical Institute Investigator. Her laboratory is interested in the pathogenic mechanisms of neurological disorders affecting learning and memory. Her research team created a mouse model with the hallmarks of human Alzheimer's disease: massive loss of neurons, the presence of neurofibrillary tangles, and accumulation of amyloid peptides in the brain, accompanied by severe memory loss. With such mice, their studies have shown how both environmental enrichment and drugs called HDAC inhibitors can restore memories seemingly lost. Memories from Tsai's own childhood, with a grandmother suffering from Alzheimer's, inspire her to seek a cure for the devastating disease.

Q: Hello, Li-Huei
When the brains of the mice were "modified" to lose memory of the platform location, was there a control group of mice that did not attend "Disney Land"? Did their memory improve over time alone?

Thank you. Al Hopfer, Arlington Heights, Illinois

Li-Huei Tsai: Hello, Al
This is a very important question. For all the experiments we do, the control group provides essential information for us to interpret the experimental data. In this case, the control group of mice who were not housed in "Disney Land" did not exhibit improvement over time.

Q: Why do Alzheimer's patients have some days clear and other days in a complete fog? Anonymous

Tsai: Dear Anonymous,
This phenomenon is known as "fluctuating memory," and it is quite common amongst Alzheimer's patients. We believe that it is due to an impairment in the communications among brain cells (neurons). Neurons "talk" to each other through numerous contact points known as synapses. These synaptic structures are massively reduced, along with the brain cells themselves, in Alzheimer's patients. However, traces of memory may still be stored in the remaining neurons and neural circuits. Thus, you can imagine the memory circuits in the patients as broken phone lines that are clear sometimes but interrupted at other times. The enrichment ("Disney Land") treatment we used in our experiments probably strengthens the communication among the remaining neurons by promoting the growth and increasing the number of synapses.

Q: Hi, Dr. Tsai

How similar are the defects your mice develop to those that human AD [Alzheimer's disease] patients exhibit? Are they similar enough that the mouse work will translate to humans?

Also, do you think that HDAC inhibitors may affect the expression of p25 and/or other proteins implicated in AD pathogenesis in order to "rescue" memories? Thanks, and I enjoyed learning about your research. Lee Montagna, Rye Brook, New York

Tsai: Hi, Lee

I would say that in many respects our mice, which are called inducible p25 (ip25) mice, closely model the pathology and symptoms of human Alzheimer's. Our ip25 mice exhibit massive neuronal/synaptic loss, reactive astrogliosis, increased beta-amyloid peptide production, and tau pathology. Furthermore, they display impairment in synaptic plasticity and memory formation.

I believe that our investigation of how HDAC inhibitors affect learning and memory defects in p25 mice is very exciting, and it provides a strong argument to further develop this approach for possible applications for humans. I certainly hope that our results will translate to humans. So far, I have no evidence to indicate that the HDAC inhibitors affect the expression of p25.

Q: I'd like to know what nutrients or medications we can take when we have some early symptoms plus a strong genetic close family history of Alzheimer's. Too often, it's chalked off as dementia. Doctors don't take my concerns seriously, or they have limited knowledge of prevention or treatments. Judie Lane, Fairfax, California

Tsai: Dear Judie,
Unfortunately, we simply do not have enough experimental data in people to answer your questions. I am not a doctor, so I really cannot tell you what to do. However, I believe that maintaining an active lifestyle and engaging in regular exercise has to be very beneficial.

Q: I have read many different theories about the mechanism of Alzheimer's disease. Have scientists now settled on the exact mechanism or the causes of this disease? What is the reason for such massive loss of neurons? How do the amyloid plaques form? Do scientists know the exact pathway? Why are the current drugs not very effective? Have you succeeded in curing the symptoms in your specially-bred mice? Thanks for your response. Ken, Barcelona, Spain

Tsai: Dear Ken,
The reason why Alzheimer's disease is difficult to crack is because it probably is a very heterogeneous disease with multiple causes. Genetic predisposition also plays an important role. However, based on human genetics, it is quite clear that increased beta-amyloid peptides in the brain play an early role in the pathogenesis of this disease. Research results from my laboratory strongly suggest that increased p25 production is probably an important factor in massive loss of neurons. The plaques are formed through increased beta-amyloid peptide production and/or decreased clearance of these peptides in the brain. I am optimistic that more effective drugs will be available in the next 5-10 years. Finally, yes, in our experiments we have been able to attenuate the symptoms in our mice using different approaches.

Q: Dr. Tsai,
I was fascinated by your research shown on NOVA's program. My mother has been dealing with a form of dementia ever since she had chemo for breast cancer. You may be familiar with it: chemobrain. Her doctors have tried many of the conventional drugs for Alzheimer's to no avail. We are trying to get her insurance company to approve provigil, which was approved by the FDA for narcolepsy, but has proven very effective in studies on patients with chemobrain. However, so far they will not approve it. Do you have any advice for her treatment, or will there be any hope for HDAC inhibitors to be available to the public in the near future? Thank you for your help! Zach Bruton, Baton Rouge, Louisiana

Tsai: Dear Zach,
Thanks for your questions. This proposed connection between chemotherapy and Alzheimer's is interesting, but not something I was aware of. As I noted in an earlier answer, I am hopeful that new, more effective therapies for Alzheimer's will be available within the next decade.

Q: Researchers at UCSB [University of California, Santa Barbara] have supposedly seen a link between the use of Ceylon cinnamon and the clearing of the tangles of Alzheimer's. Have you found any connection in your research? Ginny Doehler, Santa Barbara, California

Tsai: Dear Ginny,
I was not aware of this, and I have not used the approach in our mouse model. Thanks for writing in.

Q: A couple of years ago, UCLA was doing a human study to see if turmeric cures or prevents Alzheimer's. It was reported to work in mice. Do you know any news about this project? Also, how do you give a mouse Alzhiemer's? Dr. James Mundy

Tsai: Dear Dr. Mundy,
I am not familiar with the turmeric work. Concerning the Alzheimer's model, scientists usually create a transgenic mouse model where a particular version of a gene shown to be genetically link to Alzheimer's is forced to be expressed in mice. This usually causes the mice to manifest pathological and behavioral phenotypes that mimic certain aspects of Alzheimer's. For instance, one experimental model called APP transgenic mice have massive amyloid plaque pathology along with learning impairment and another, called Tau transgenic mice, develop neurofibrillary tangle pathology. Mice expressing both APP and Tau were also created that exhibit both the plaque and tangle pathology.

Q: What is it about the brain/brain chemistry of mice that make them so suited for research in human brain diseases? Martin Askjaer, Denmark

Tsai: Dear Martin,
The mouse brain contains most of the brain circuits that we know exist in the human brain. The major reason for using the mouse as a model organism to study human diseases, however, is because of the power of modern genetic science. Scientists can create mouse models like those mentioned in the previous answer. We can bioengineer mice to overexpress disease genes in a particular group of cells to model various diseases. It is also possible to eliminate the expression of certain genes in mice. So far, the creation of such animal models for various diseases has not been possible in other mammals.

Q: Is there anything I can do or take that will restore or at least improve my short-term memory? Joseph Bauman, Boca Raton, Florida

Tsai: Dear Joseph,
My recommendation to you, and to others as well, would be to keep yourself busy and to undertake regular exercise.

Q: Is Alzheimer's hereditary? Students of the Kelly Road Secondary School, grade 12, Prince George, British Columbia, Canada

Tsai: Dear students of Kelly Road,
The familial (hereditary) form of Alzheimer's disease accounts for less than five percent of all patients. Mutations in three genes, and only three genes, can cause this hereditary form of Alzheimer's: APP, PS1, and PS2. However, it is also becoming clear that there are other genetic factors that may affect the risk for developing Alzheimer's, including the ApoE4 alleles and some genes that have yet to be identified. If one has a "bad" allele, there is increased risk for Alzheimer's, but this does not necessarily mean you will develop the disease. Environmental factors, diet, and lifestyle may all affect the outcome.

Q: A relative of mine has early Alzheimer's. Should she live in an apartment with a caregiver or at a facility with others? Anonymous

Tsai: Dear Anonymous,
I would prefer to keep myself in an environment where I could be exposed to, and interact with, many people and keep myself mentally and physically occupied. Best wishes.

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