Neural Stem Cell Transplant-Induced Effect on Neurogenesis and Cognition in Alzheimer Tg2576 Mice Is Inhibited by Concomitant Treatment with Amyloid-Lowering or Cholinergicα7 Nicotinic Receptor Drugs

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.

Essential oils from two Allium species exert effects on cell proliferation and neuroblast differentiation in the mouse dentate gyrus by modulating brain-derived neurotrophic factor and acetylcholinesterase

“…It has been reported that enhanced hippocampal cell proliferation and neurogenesis improves memory deficits and memory impairments [45–48]. In this study, we observed significant increases in the number of cells positive for Ki67 and DCX, which are markers for proliferating cells and neuroblasts, respectively, in the subgranular zone of the dentate gyrus in the GO-treated group.…”

Effects of neural stem cell transplantation in Alzheimer’s disease models

“…Notably mNSCs alter microglia from a pro-inflammatory state to an anti-inflammatory state, leading to a decrease in Aβ level through an increase in NEP and phosphorylated tau levels. These effects have yet to be shown in hNSC studies [50,51] (Table 2).…”

“…In the transplant region, many α7 nAChR-expressing astrocytes were found, suggesting that such astrocytes are involved in repairing damaged neurons and growth of new ones. Despite combined treatment using both drugs and NSCs, positive effects such as neurogenesis and cognition recovery was not sustained [50] (Table 2).…”

Stem cells as a promising therapeutic approach for Alzheimer’s disease: a review

“…Altogether, transplanted NSCs mitigate neuroinflammation, enhance neurogenesis, promote synaptogenesis, and rescue cognitive functions of AD animal models (Yang et al 2016;Lilja et al 2015;Ager et al 2015;Zhang et al 2015b). Moreover, NSC transplantation resulted in modulation of cross talk between NSCs and endothelial cells (Li et al 2006).…”