Brain Environment and Alzheimer’s Disease Mutations Affect the Survival, Migration and Differentiation of Neural Progenitor Cells

Virve      Karkkainen; Johanna      Magga; Jari      Koistinaho; Tarja      Malm

Abstract

Enhancement of neurogenesis and stem cell transplantation are potential therapies for neurodegenerative diseases. In Alzheimer’s disease (AD) newborn neural cells and the transplanted cells encounter a diseased brain where the accumulation of toxic amyloid-β (Aβ) peptides disturbs normal functions and interactions of brain cells. In addition, ADlinked mutatations in newborn neurons or autologously transplanted neural progenitor cells (NPCs) are likely to affect the fate of these cells. Here we analyzed the effect of AD-linked APdE9 mutant on NPCs in culture and by isolating NPCs from APdE9 transgenic mice and transplanting them into APdE9 and wild type mouse brain. We show that the brain environment in APdE9 mutant mice reduced astrocytic differentiation but increased the survival and migration of NPCs in vivo. APdE9 mutation of NPCs increased neuronal differentiation also in vitro. Instead extracellular Aβ42 peptide decreased the survival, neuronal differentiation and migration of NPCs in vitro, whereas Aβ40 had an opposite effect. NPC transplantation induced brain neurogenesis, which was not altered in Aβ burdened APdE9 brain or by APdE9 mutant in NPCs. Thus, AD-linked mutations in newborn neural cells or NPCs do not compromise the utilization of enhanced neurogenesis or autologous NPC transplantation as potential therapies. The results suggest that combining the treatments resulting in reduced Aβ42 and enhanced neurogenesis may be one therapeutic approach to be explored in AD.

Keywords: Abeta, Alzheimer’s disease, differentiation, migration, neural progenitor cell, stem cell, transplantation, amyloid precursor protein, phenotype, neurospheres.