Basic approach to neuro-replacement therapy: Alzheimer's

Sugaya, Kiminobu

Abstract

This proposal is to respond the research topic 5. Stem Cells. It has recently been reported that the adult human brain retains multipotent progenitors, suggesting that regeneration of CNS cell types may occur throughout life. The feasibility of engraftable human neural progenitor (HNPs) has been reported and neuroreplacement therapies are increasingly targeting neurodegenerative diseases. These facts stimulate us to propose our current study, using HNPs as a source of cells for transplantation therapy in Alzheimer's disease (AD). Since the loss of basal forebrain cholinergic neurons may involved in the deterioration of memory in AD, we will investigate the replacement of the cholinergic cells by engrafted HNPs. We hypothesized that transplanted HNPs will migrate and differentiate into the necessary cells (cholinergic neurons and glial cells) by the factor or cue existing in the brain with cholinergic lesion. Stem cells are often defined as self-renewing and multipotent, with the capacity to generate diverse types of differentiated cells. Neural stem-like cells have been isolated from the embryonic and adult rodent central nervous system (CNS) and propagated in vitro in a variety of culture systems. Using serum-free condition, we have been able to expand HNPs in vitro without losing its multipotency, which offers a well-characterized and effective source of transplantable material as a favorable alternative to using human fetal neuronal tissues. We recently succeeded in the improvement of cognitive function of aged rats using the transplantation of these in vitro expanded HNPs cells. In our study the cells, which labeled with BrdU, migrated into wide variety of the brain region and differentiated into a various kinds of cells according to the environmental cue of the host brain. In this current proposal, we will apply same strategy for in vitro expansion and transplantation procedure of the HNPs used in the previous study to well established basal cholinergic neuronal lesion models. We will analyze the cognitive function of transplanted animals by Morris water maze, and the migration and differentiation of HNPs by multiple labelings of immunofluorescent histochemistry. This proposed study will build a base of our future grant proposal, which involves characterization and manipulation of the factors released from the host brains to understand the requisite differentiation conditions of HNPs under neurodegenerative condition. This line of studies will greatly facilitate the transplantation and/ or generation of CNS phenotypes from HNPs in therapeutic strategies for AD.