Juan Sanchez-Ramos, Ph.D., M.D.

Triggering New Neuron Production in Adult Hippocampus with NeuroD

Loss of brain Cells is a common pathological event in many brain diseases. The brain has the capacity to generate new neurons (neurogenesis) in adult life, but the rate of new neuron production is inadequate to replace the significant loss of brain cells that occurs in neuro-degenerative diseases such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease (HD), and in neurologic "accidents" such as head trauma, spinal cord injury and stroke. One of the major challenges in brain research is to discover therapies to enhance brain self-repair by promotion of neurogenesis, neuronal differentiation and functional integration of new neurons into existing networks.

Production of new neurons in the adult hippocampus can be positively or negatively modulated by many factors such as aging, exercise, and growth factors. More recently the study of transcription factors, that control the production of proteins molecules by interacting with DNA, has suggested novel approaches to promote neurogenesis. NeuroDl is a key transcription factor that appears to play an important role in controlling the formation of new neurons during early development of the nervous system and throughout life in the adult hippocampus and other neurogenic zones of the brain.

Using the techniques of molecular biology we have incorporated the human gene for NeuroDl into a ring of DNA (a plasmid). This construct (abbreviated as hNeuroDl/GFP) was used to transfect a human fetal astro-glial cell line. This immortalized cell line does not normally express NeuroDl and does not develop into neurons. Successful transfection of the glial cells was confirmed by the appearance of green florescence of the attached "reporter gene", GFP (Green Fluorescent Protein) located within the same cells that expressed the NeuroDl protein. We were able to demonstrate that the hNeuroDl/GFP transfected cells turned on a set of genes that are seen during neuronal differentiation. Under the microscope, these cells also began to show proteins normally seen in young developing neurons.

To expand these findings towards research with potential therapeutic utility for AD, we plan to test whether neural stem cells that reside in the adult hippocampus can be driven into new neurons by experimental over-expression of NeuroDl. More specifically, we postulate that expression of NeuroDl in neural stem/progenitor cells (NSC) in mice with an injured hippocampus will limit injury-induced glial proliferation and "scarring" by redirecting the cells into new neurons.