Short report

Neural progenitor cells attenuate inflammatory reactivity and neuronal loss in an animal model of inflamed AD brain

Jae K Ryu^1* , Taesup Cho^2* , Yu Tian Wang² and James G McLarnon¹

¹  Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

²  Brain Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

author email corresponding author email* Contributed equally

Journal of Neuroinflammation 2009, 6:39doi:10.1186/1742-2094-6-39

Published:	23 December 2009

Abstract

Background

Transplantation of neural progenitor cells (NPC) constitutes a putative therapeutic maneuver for use in treatment of neurodegenerative diseases. At present, effects of NPC transplantation in Alzheimer's disease (AD) brain are largely unknown and a primary objective of this work was to demonstrate possible efficacy of NPC administration in an animal model of AD. The benefits of transplantation could involve a spectrum of effects including replacement of endogenous neurons or by conferring neuroprotection with enhancement of neurotrophic factors or diminishing levels of neurotoxic agents. Since chronic inflammation is a characteristic property of AD brain, we considered that transplantation of NPC could have particular utility in inhibiting ongoing inflammatory reactivity. We have tested intrahippocampal transplantation of NPC for efficacy in attenuating inflammatory responses and for neuroprotection in beta-amyloid (Aβ_1-42) peptide-injected rat hippocampus.

Methods

Spheres of neural progenitor cells were grown from dissociated telencephalon tissue of rat embryos. NPC were infected with lentiviral vector green fluorescent protein (GFP) with subsequent cell transplantation into rat hippocampus previously injected (3 d prior) with Aβ_1-42 peptide or PBS control. Immunohistochemical analysis was carried out (7 d post-NPC transplantation, 10 d post-peptide/PBS injection) for GFP, microgliosis (Iba-1 marker), astrogliosis (GFAP marker), neuron viability (MAP-2 marker) and levels of the proinflammatory cytokine, TNF-α.

Results

Successful infection of cultured NPC with lentiviral vector green fluorescent protein (GFP) was demonstrated prior to cell transplantation into rat hippocampus. In vivo, immunohistochemical staining showed migration of GFP-positive cells, in a region of dentate gyrus between Aβ_1-42/PBS injection site and NPC transplantation site, was increased ×2.8-fold with Aβ_1-42 compared to PBS injection. Double immunostaining in peptide-injected brain indicated GFP association with nestin and GFAP, but not MAP-2. Cell-specific immunostaining showed marked increases in microgliosis and astrogliosis in Aβ_1-42-injected brain (respective increases of ×4.3- and ×4.6-fold compared with PBS injection). NPC transplantation significantly reduced microgliosis (by 38%) but not astrogliosis in peptide-injected hippocampus. The proinflammatory cytokine TNF-α was elevated by 6.7-fold (peptide vs PBS injection) with NPC administration attenuating levels of TNF-α (by 40%). Peptide-injected brain demonstrated neuronal loss (MAP-2 staining reduced by 45% vs PBS injection) with NPC transplantation effective in conferring neuroprotection (26% recovery of neurons).

Conclusions

These findings indicate efficacy for NPC transplantation in an animal model of AD with effects consistent with cellular actions to attenuate inflammatory reactivity induced by intrahippocampal peptide injection.