Saul Villeda, PhD
Saul Villeda, PhD
Adult neural stem cell in aging and cognition
Aging alters both the regenerative capacity and functional integrity of the adult brain, and as a result steadily drives cognitive impairments and susceptibility to neurodegenerative disorders in healthy individuals. In fact, aging remains the single most predominant risk factor for dementia-related neurodegenerative diseases in the elderly, such as Alzheimer’s disease. Now considering the rate at which the human population is currently aging, it becomes critical to identify ways by which to maintain cognitive integrity by protecting against, or even counteracting, the effects of aging. Our lab will investigate the cellular and molecular mechanisms that contribute to brain aging, as well as those that promote the rejuvenation of the old brain. The ultimate goal of our work is to better understand how to ameliorate age-related cognitive dysfunction by harnessing the latent plasticity still remaining within the old brain.
Stem cells have been the focus of numerous scientific endeavors due to their potential for mediating enhanced tissue repair, regeneration from degenerative diseases, and amelioration of age-related organ dysfunction. The possibility of harnessing stem cells to reverse normal aging raises the question as to how the aging process modulates tissue specific stem cell activity. In the central nervous system, investigating the effect of aging on neural stem/progenitor cell (NPC) function is of particular interest due to the associated onset of cognitive impairments, and lack of neural repair in response to neurodegenerative diseases. Previously, we discovered that molecular changes occurring in the aging systemic milieu negatively regulate NPC function and cognition. Furthermore, we identified a subset of systemic immune factors, as potential regulators of neurogenesis and cognitive function. Interestingly, immune signaling has emerged as a key player in the negative regulation of adult neurogenesis. Thus, one aim of our research is to investigate how immune-related molecular changes in the aging systemic milieu regulate NPC function and associated cognitive processes. We hope that by investigating mechanisms underlying impairments in NPC function, we can better understand how to ameliorate age-related cognitive dysfunction in the old brain.
Work by our lab, and others, has also demonstrated that the aging central nervous maintains a certain amount of latent plasticity. Furthermore, work using heterochronic parabiosis - in which the circulatory system of an old and young animal are connected – indicate that this latent plasticity can be tapped into to reverse age-related impairments in neural stem cell function in the old brain. Therefore, a second aim of our research is to begin to elucidate the cellular and molecular mechanisms underlying this latent plasticity and identify key molecules that can promote cognitive enhancements late in life. We combine heterochronic parabiosis and cognitive testing with gain and loss of function experiments to investigate these mechanisms in vivo.
S.A. Villeda, J. Luo, K.I. Mosher, B. Zou, M. Britschgi, G. Bieri, T.M. Stan, N. Fainberg, Z. Ding, A. Eggel, K.M. Lucin, E. Czirr, J-S. Park, S. Doupres-Couillard, L. Aigner, G. Li, E.R. Peskind, J.A. Kaye, J.F. Quinn, D.R. Galasko, X.S. Xie, T.A. Rando, and T. Wyss-Coray. 2011. The aging systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 477(7362):90-4
M. Moriyama, T. Fukuhara, M. Britschgi, Y. He, R. Narasimhan, S. Villeda, H. Molina, B.T Huber, M. Holers, and T. Wyss-Coray. 2011. Complement receptor CR2/CD21 is expressed by neuronal progenitor cells and regulates adult hippocampal neurogenesis. Journal of Neuroscience. 31(11):3981-3989
V.M. Renault, V.A. Rafalski, A. Morgan, D.A. Salih, J.O. Brett, A.E. Webb, S. A. Villeda, P.U. Thekkat, C. Guillerey, N.C.Denko, T.D. Palmer, A.J. Butte, and A. Brunet. 2009. FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell. 5(5):527-39
S. Villeda and T. Wyss-Coray. 2008. Microglia – a wrench in the running wheel? Neuron. 59(4): 527-9.