Taos: Disease, Drug Development, and Adult Neurogenesis

This is Part 2 of a two-part series. See also Part 1.

17 February 2011. It is now firmly established that neurogenesis takes place in two small regions of the mammalian adult brain: the subventricular zone just underneath the brain ventricles and the subgranular zone of the dentate gyrus in the hippocampus. Research suggests that neurons born to those regions in adult brains are functional and integrate into neural networks in some circumstances. But does adult neurogenesis have any relevance to neurological/neurodegenerative disorders, such as depression or Alzheimer’s disease, and could neurogenesis represent a novel target for therapeutics? These ideas were discussed at the inaugural Keystone Symposium on Adult Neurogenesis, held 9-14 January 2011, in Taos, New Mexico. While this branch of neuroscience is still in its infancy, there were hints that neurogenesis may play an important role in adult diseases.

Steven Goldman, University of Rochester Medical Center, New York, is known for his studies of the songbird model of adult neurogenesis. Goldman described a BDNF/noggin treatment that induced neurogenesis and delayed disease onset and extended survival in a mouse model of Huntington’s disease. Hans-Peter Lipp, University of Zurich, Switzerland, challenged some widely accepted assumptions. He noted that adult hippocampal neurogenesis has been demonstrated in only six out of the 26 mammalian orders. Contrary to the axiom that running increases neurogenesis in lab mice, he found no neurogenesis in wild wood mice. Lipp is currently investigating whether age-related reduction of hippocampal neurogenesis might represent a stabilizing effect during habituation, and whether a temporary increase in the birth of hippocampal neurons may reflect habit breaking and the learning of new routines.

Günther Zupanc, Northeastern University, Boston, Massachusetts, and Tatyana Dias, Edinburgh University, United Kingdom, presented zebrafish as a model for adult neurogenesis research. Dias, a graduate student, addressed spinal cord neurogenesis and excited the audience with a video clip that showed adult zebrafish that recovered their ability to swim several weeks after the scientists had completely transected their spinal cord. Dias suggested that Notch signaling, which reduced motor neuron numbers during spinal cord neurogenesis in the fish, may account for some limited regenerative potential in mammalian spinal injury as well.

Many neurological disorders have been associated with diminished adult neurogenesis. This correlation has left researchers wondering if that diminution contributes to disease pathology and etiology, and also, if enhancing neurogenesis could be a viable therapeutic strategy.

It has been known for many years that ischemic stroke increases adult neurogenesis (Jin et al., 2001). Furthermore, the brain’s natural neurogenic repair mechanisms induce production, migration, and functional integration of neuroblasts into damaged tissue, explained Olle Lindvall, University of Lund, Sweden. Stroke recovery, however, requires not only an adequate supply and survival of neuroblasts in the damaged tissue, but also functional synaptic connectivity of new neurons. Lindvall’s data demonstrated that an inflammatory response following stroke regulates such synaptic development in adult-born neurons.

Unlike stroke, there is no evidence of reactive neurogenesis in Parkinson’s disease (PD). No new neurons have been reported in the adult substantia nigra—the primary site of dopaminergic neuronal loss in PD. Rather, decreased neurogenesis was observed in autopsy PD tissue (Höglinger et al., 2004). Could the reduced generation of newborn neurons in neurogenic regions contribute to the development of some non-motor symptoms in PD? Jürgen Winkler, Universitätsklinikum, Erlangen, Germany, demonstrated that downregulating α-synuclein (the pathological protein typically found in Lewy bodies) restores neurogenesis in the hippocampus and olfactory bulb of mice. This implies that impaired hippocampal and olfactory bulb neurogenesis may be associated with non-motor symptoms in PD, such as anxiety, depression, and hyposmia (poor ability to smell). His data implicate the Notch signaling pathway as impairing the survival of adult-born neurons in transgenic PD models. Winkler also demonstrated that the administration of certain growth factors could promote migration of newly generated neurons to lesioned tissue. This work hints that newly generated neuroblasts may help to restore dysfunctional striatal circuitry and impaired motor function.

Though the hippocampus is best known for its role in learning and memory, it is also active in stress and emotion, mood, and anxiety. For example, patients with chronic major depression have smaller hippocampi. Rene Hen and Amar Sahay, Columbia University, New York, presented work supporting the notion that impaired adult neurogenesis can explain aspects of depression. These studies demonstrated that genetic expansion of adult neurogenesis in mice decreased anxiety-like behavior, under certain conditions, raising the question of whether stimulation of neurogenesis could provide a future therapy for anxiety disorder. Mi-Hyeon Jang, Johns Hopkins University, Baltimore, Maryland, then suggested that secreted frizzled-related protein-3 (sFRP3), a Wnt inhibitor, is a potential therapeutic target for depression treatment. Jang observed that electroconvulsive stimulation of the hippocampal neuronal circuitry downregulates sFRP3 expression and accelerates AHN. He noted that chronic antidepressant treatment suppresses sFRP3 expression in the DG.

The final session looked toward the future of neuronal repair, covering the latest approaches and technologies for translating neural progenitor proliferation to clinical applications. Vanderhaeghen, University of Brussels, Belgium, discussed embryonic stem (ES) cells and other pluripotent stem cells as tools for modeling and treating human disease. He presented striking in vitro data that demonstrated the sequential generation of a diverse population of neurons from stem cells, including those that seemed to be bona fide cortical neurons. Grafting these neurons into the cerebral cortex led to proper axonal projections. Carrolee Barlow, Brain Cells Inc., San Diego, California, demonstrated how drugs that can promote neurogenesis have been identified by in vitro and in vivo screening of neurogenesis and behavioral impacts in animals. From such screens, she selected drug candidates including, Buspar (buspirone) and melatonin. She reported that Buspirone alone, an agonist for the 5HT-1 serotonin receptor, upregulates both gliogenesis and neurogenesis, whereas the combination of buspirone and melatonin resulted in upregulation of neurogenesis without the increase in glia. Based on the preclinical findings, the investigators studied if the combination of buspirone and melatonin could be used to treat patients with major depressive disorder. She showed the positive clinical data from a double-blind placebo-controlled study demonstrating that the combination of Buspar and melatonin can help ameliorate depression symptoms in patients. Anders Haegerstrand, NeuroNova AB, Stockholm, Sweden, is researching neurogenic and neuroprotective drugs for treatment of a wide range of neurodegenerative diseases. He found that PDGF-BB promotes proliferation of progenitors in SVZ as well as improves symptoms in animal models of PD. Haegerstrand also presented a drug-delivery system which is currently used to deliver PDGF to patients with PD. It features a pump running directly into one of the lateral ventricles in the brain. The drug evenly disperses throughout all ventricles by virtue of cerebrospinal fluid flow. Haegerstrand also showed that Exendin-4, a glucagon-like peptide 1 agonist, dose-dependently increases neuron proliferation in the SVZ and hippocampus. Exendin-4 is currently in clinical trials for AD and PD (see ARF related news story).

Neural Stem Cells in Alzheimer’s Disease
Frank LaFerla, University of California, Irvine, delivered a rapid-fire talk on the translation of science to medicine, mouse to (wo)man, and disease to therapy. LaFerla addressed one of the fundamental motives behind the investigation of adult neurogenesis—the therapeutic potential. Likening the AD hallmarks of β amyloid (Aβ) plaques and tau-laden neurofibrillary tangles to "toothpaste squeezed from a tube," LaFerla said that once they are established, it seems nearly impossible to reverse the process by means of stem cell therapy. Consequently, LaFerla described a prophylactic approach using NSC-derived BDNF that exploits the benefits of NSCs without requiring cell transplantation. Results demonstrated enhanced hippocampal synaptic plasticity and ameliorated cognitive function without altering Aβ or tau pathology.

LaFerla reminded the audience that Alzheimer’s disease destroys up to 50 percent of the 100 billion human brain cells and the 100 trillion synapses they form. He believes that a more promising direction of stem cell research lies in identifying a range of cell lines derived from different ethnic groups that could be used universally among diseased patients. LaFerla surmised that the medical objective of cell replacement is at odds with the realities of adult neurogenesis. "Neural stem cell therapies likely won’t work to combat Alzheimer’s, " LaFerla said, "but we owe it to our patients to leave no stone unturned."

In summary, adult neurogenesis is a complex process whose medical relevance is speculative at present and will only be revealed with a greater understanding of how the brain works. In the meantime, NSCs present a unique opportunity to understand neural plasticity and the anomalous phenomenon of adult neurogenesis.—Lansdale Henderson.

Lansdale Henderson is an undergraduate student working in Jonathan Kipnis’s lab at the University of Virginia.

This is Part 2 of a two-part series. See also Part 1.

To view commentaries, primary articles and linked stories, go to the original posting on Alzforum.org here.

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