Neural Stem Cell Transplant-Induced Effect on Neurogenesis and Cognition in Alzheimer Tg2576 Mice Is Inhibited by Concomitant Treatment with Amyloid-Lowering or Cholinergic α7 Nicotinic Receptor Drugs.

Anna M Lilja,Amelia Marutle,Agneta Nordberg,Jennie Röjdner,Linn Malmsten,Sven Ove Ögren,Larysa Voytenko,Alexei Verkhratsky

doi:10.1155/2015/370432

Abstract

Stimulating regeneration in the brain has the potential to rescue neuronal networks and counteract progressive pathological changes in Alzheimer's disease (AD). This study investigated whether drugs with different mechanisms of action could enhance neurogenesis and improve cognition in mice receiving human neural stem cell (hNSC) transplants. Six- to nine-month-old AD Tg2576 mice were treated for five weeks with the amyloid-modulatory and neurotrophic drug (+)-phenserine or with the partial α7 nicotinic receptor (nAChR) agonist JN403, combined with bilateral intrahippocampal hNSC transplantation. We observed improved spatial memory in hNSC-transplanted non-drug-treated Tg2576 mice but not in those receiving drugs, and this was accompanied by an increased number of Doublecortin- (DCX-) positive cells in the dentate gyrus, a surrogate marker for newly generated neurons. Treatment with (+)-phenserine did however improve graft survival in the hippocampus. An accumulation of α7 nAChR-expressing astrocytes was observed around the injection site, suggesting their involvement in repair and scarring processes. Interestingly, JN403 treatment decreased the number of α7 nAChR-expressing astrocytes, correlating with a reduction in the number of DCX-positive cells in the dentate gyrus. We conclude that transplanting hNSCs enhances endogenous neurogenesis and prevents further cognitive deterioration in Tg2576 mice, while simultaneous treatments with (+)-phenserine or JN403 result in countertherapeutic effects.

Highlights

In recent years expectations have been raised that stem cell replacement therapy could be used as a therapeutic approach to compensate for lost or damaged neuronal cells and to restore functionality in brain areas affected by chronic neurodegenerative diseases, such as Alzheimer disease (AD)
We have earlier proposed that the pathophysiological environment in the AD brain could have adverse effects on neurogenesis [3, 4], and it is suggested that the memory deficits observed in AD may be linked to Neural Plasticity alterations in hippocampal neurogenesis as reviewed in [5,6,7]
The subsequent effects on human neural stem cell (hNSC) transplant survival, endogenous neurogenesis, and the involvement of a subpopulation of astroglia, the α7 nAChRexpressing astrocytes in the neurogenic niche of the dentate gyrus (DG), were determined

Summary

Introduction

In recent years expectations have been raised that stem cell replacement therapy could be used as a therapeutic approach to compensate for lost or damaged neuronal cells and to restore functionality in brain areas affected by chronic neurodegenerative diseases, such as Alzheimer disease (AD). We applied a combinational therapeutical approach to investigate whether drugs with specific and distinct mechanisms of action on Aβ production and α7 nAChRs, respectively, could enhance neurogenesis and improve memory in human neural stem cell- (hNSC-) transplanted transgenic mice overexpressing the human amyloid precursor protein with the double Swedish mutation, Tg2576 This animal model is phenotypically similar to the prodromal stage of AD, and, at 6 to 9 months of age, Tg2576 mice demonstrate elevated levels of Aβ oligomers in the brain but no Aβ plaques, increased astrogliosis as well as impairment of synaptic function, and learning and memory deficits [12,13,14,15]. The subsequent effects on hNSC transplant survival, endogenous neurogenesis, and the involvement of a subpopulation of astroglia, the α7 nAChRexpressing astrocytes in the neurogenic niche of the dentate gyrus (DG), were determined

Materials and Methods

Results

Discussion