26 November 2007. At the 37th conference of the Society for Neuroscience, held earlier this month in San Diego, Sangram Sisodia’s group at the University of Chicago, Illinois, presented new data that exemplify how the expanding field of environmental enrichment and adult neurogenesis has inspired AD research. Sisodia presented a special twist on this emerging story with experiments supporting the idea that the presenilin mutations that cause familial AD lead to defects in hippocampal neurogenesis (Wen et al., 2002; Wen et al., 2004). A growing number of laboratories are probing different aspects of how environmental enrichment, or other forms of physical and mental exercise, stimulate the growth of neural precursor cells in mice, dogs, and even humans. The goal is to both understand underlying mechanisms and their relevance to aging and AD, and to build a body of knowledge upon which to base therapeutic interventions. And helping to narrow the leap from beast to human, a paper in Science offered news on a method to image neural progenitor cells in the brains of people.
That environmental enrichment boosts learning and memory goes back to an original observation by none other than Donald Olding Hebb (Hebb, 1947), who is better known for his theory of synaptic plasticity. That hippocampal neurogenesis continues into adulthood in rodents and mammals is more recent knowledge, but established, as well (e.g. Lie et al., 2004). Sisodia’s lab began this line of research when Orly Lazarov, then in his lab, discovered that keeping mice in cages filled with toys and climbing structures reduced amyloid-β levels and deposition in APP/PS1-transgenic mice (Lazarov et al., 2005).
In San Diego, Sisodia and postdoc Karthik Veeraraghavalu presented data on the potential role of presenilin in mediating effects of environmental enrichment. Sisodia began by establishing that mice living in the “fun” cages had more neurogenesis in their hippocampi. The researchers obtained absolute numbers by cutting the hippocampus into series of slices and counting every BrdU-labeled cell. The most avid users of the running wheel seemed to lead the pack. By contrast, adult mice expressing either the δE9 or the M146L FAD mutations in presenilin 1 derived no benefit from environmental enrichment. They did have some neurogenesis in their hippocampus, but their BrdU counts stayed flat no matter how eagerly they scampered over their colorful playthings, suggesting that presenilin somehow influences the enrichment-induced proliferation of neural progenitor cells (NPCs).
The scientists asked if this difference arose from within the neural precursors or a different cell type. To do that, they developed neurosphere cultures of hippocampal NPCs and primary microglia. Intriguingly, they found that the effect appeared to come from the glia. NPCs from human wild-type PS1 transgenic mice proliferated when cultured with microglia from wild-type PS1 mice, but failed to do so when cultured with microglia from mice expressing FAD-linked PS1, Sisodia reported. Moreover, the differentiation of wild-type PS1 NPCs toward neurogenic lineages was markedly inhibited when they were co-cultured with microglia from mutant PS1 mice.
The conditioned medium from PS1 microglia fully recapitulated the wild-type NPC responses in co-culture assays. This suggests that the glia secrete some mystery factors that are dependent on expression of presenilin 1. Analysis of the cytokine and chemokine profile of wild-type versus mutant microglia generated a list of polypeptides whose mRNA and protein levels changed, including CXCL16, MCP-1, eotaxin, and others, Sisodia reported. While still evolving, this work suggests that environmental enrichment activates normal microglia to release proteins that support the proliferation and neurogenesis of neural precursors in the hippocampus. Microglia expressing these pathogenic presenilin mutations do not respond to enrichment in this way, suggesting that they need proper presenilin function to translate the environmental stimulus into a changed chemokine output.
But like everything in the brain, one cell type does not tell the whole story. NPCs expressing either of these two FAD presenilin mutations show cell-autonomous deficits, as well. On a poster, Veeraraghavalu showed that self-renewal and differentiation of these NPCs were impaired in neurosphere cultures taken from the subventricular zone of these mice. In those cells, the problem may have to do with Notch, a well-studied substrate of presenilin. The NPCs do express the Notch signaling machinery, and priming this pathway by expressing downstream target genes revived their flagging proliferation, the Chicago scientists reported. Further experiments also pointed to the interpretation that a partial loss of Notch processing may account for the defects of these mutant NPCs.
When cell-based and animal research develop mechanistic plot lines, the question of how pertinent this is to human aging and disease invariably arises. On this question, a collaboration of scientists at the State University of New York (SUNY) at Stony Brook and Cold Spring Harbor Laboratories on Long Island, NY, just handed the field a cool new tool. Led jointly by Mirjana Maletic-Savatic and Grigori Enikolopov, first author Louis Manganas and others reported in the November 9 issue of Science their development of the first biomarker to identify NPCs non-invasively in the brain. Using proton nuclear magnetic resonance spectroscopy (1H-NMR), the scientists characterized in vitro a lipid metabolite specific to NPCs. Then they moved to a complementary method that is suitable for live tissue imaging, that is, 1H-MRS done in an MRI scanner. This enabled them to identify NPCs in the hippocampus, first of rats, then of people. Manganas and colleagues detected the NPC biomarker in the hippocampus of adults and also looked at changes with age by imaging preadolescents, adolescents, and adults (yes, you guessed right: levels dropped off quite steeply by one’s thirties). The data gathered so far with this method confirm prior findings that demonstrated a small but continuing trickle of neurogenesis in adult life in humans.
If confirmed, this biomarker could help analyze NPCs and evaluate the efficacy of therapeutic interventions in a range of neurological and psychiatric disorders, the authors write. A press release issued by Cold Spring Harbor Laboratories quotes Walther Koroshetz, deputy director of the Neurological Disorders and Stroke, as saying: “The ability to track these cells in living people would be a major breakthrough in understanding brain development in children and continued maturation of the adult brain. It could also be a very useful tool for research aimed at influencing NPCs to restore or maintain brain health.”—Gabrielle Strobel.
Manganas LN, Zhang X, Li Y, Hazel RD, Smith SD, Wagshul ME, Henn F, Benveniste H, Djuric PM, Enikolopov G, Maletic-Savatic M. Magnetic resonance spectroscopy identifies neural progenitor cells in the live human brain. Science. 2007 Nov 9;318(5852):980-5. Abstract
Choi SH, Veeraraghavalu K, Lazarov O, Marler S, Ransohoff RM, Ramirez JM, Sisodia SS. Non-cell-autonomous effects of presenilin 1 variants on enrichment-mediated hippocampal progenitor cell proliferation and differentiation. Neuron. 2008 Aug 28;59(4):568-80. Abstract