Interesting experiments on Rett syndrome and on aging

I spoke at a meeting of the PsychoNeuroImmunology Research Society in Chicago in June and heard several very intriguing talks. Jonathan Kipnis from the Univ. of Virginia presented new findings on a mouse model of Rett syndrome that suggest a potential novel avenue of therapy. As discussed in Chap 9 of the book, Rett patients display some of the symptoms of autism, although there are many additional symptoms as well. The disorder is caused by mutations in the gene MeCP2. In the mouse model, this gene is inactivated, and the mice display learning and other deficits, and their lifespan is much shorter than normal (“wild type”) mice. The widespread symptoms of Rett in many organs are thought to be due to the importance of MeCP2 in those several organs, in addition to the brain. Kipnis had the novel idea of seeing what would happen when normal MeCP2 is restored in the immune system by treating the MeCP2 mutant mice with bone marrow transplants taken from wild type mice. Kipnis reported that this rather straightfoward treatment allowed the treated mice to live much longer than the mutant mice without the treatment, and they also perform much better in some behavioral tests, although the tests used were not particularly relevant to autism. The restoration of normal MeCP2 occurred not only in the immune system, but also in the particular population of cells in the brain called microglia. It is known that these cells can be derived from stem cells in the bone marrow, and certain parts of the mutant mouse brains displayed repopulation by wild type microglia following the bone marrow transplant. Thus, it is possible that the key action of this MeCP2 restoration could be in the brain or in the immune system, or in both. Since such transplantation is fairly safe, one wonders if a clinical trial could be under consideration.

Another fascinating talk was by Tony Wyss-Coray from Stanford. He studies Alzheimer’s disease (AD) and aging. It is known that the most important risk factor for AD is age, and it is also clear that the production of new neurons in the brain slows down dramatically with age. Wyss-Coray asked the novel question: could there by systemic changes that affect the brain – are there molecules that increase in the blood of the elderly that slow down the production of new neurons in the brain, and thereby cause deficits in learning and memory? He first did a parabiosis experiment in which a young and an old mouse are surgically linked together like Siamese twins so that they share a common circulation. Amazingly, this led to a striking drop in new neurons in the young mouse brain, and an increase in new neurons in the old mouse brain. He then looked for molecules in the blood of the old mouse and identified a chemokine (this is a family of small proteins related to the cytokines discussed throughout my book) called CCL11 (also known as eotaxin), which, when injected into young mice decreased the production of new neurons and impaired learning and memory. Thus, the increase in eotaxin in the blood that occurs during aging appears to be sufficient to cause some of major problems that are found in the brains of old mice. These results immediately suggest experiments in which eotaxin activity is blocked or its levels lowered to see how many effects of aging can be inhibited! It is also interesting that a chemokine is the key factor because it is well known that inflammatory-like changes are part of aging, both in the brain and in the circulation. Once again, the brain-immune connection is critical for understanding critical biomedical issues. This study has recently been published (Villeda et al., Nature 477:90, ’11).

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