Modulating cognitive deficits and tau accumulation in a mouse model of aging Down syndrome through neonatal implantation of neural progenitor cells

摘要

Although Down syndrome (DS) is primarily considered as a pediatric disorder, all DS patients incur Alzheimer's disease (AD)-like pathology and about 60% develop an additional AD-like dementia by 30-40. years of age. Cognitive and neuroanatomical changes in DS are least compromised perinatally, indicating there may be an opportunity to modulate their cognitive and neuroanatomical development during aging, preventing or postponing the onset of AD. To this end, neural progenitor cells (NPC) or saline were implanted into the hippocampus of neonatal DS-modeling (trisomic Ts65Dn) mice and non-DS (disomic Ts65Dn) age-matched mice. Twelve months later, implanted and unimplanted mice were assessed for long-term survival of NPC, for cognitive function, hippocampal cell density, and the presence of extracellular tau accumulation. Implantation of NPC in trisomic mice improved learning and memory as assessed by conditioned taste aversion testing, but not on the novel object recognition task. Trisomic mice given saline control injections improved performance on both cognitive tasks compared to unimplanted trisomic mice. In contrast, disomic mice, implanted with either saline or NPC, were impaired in both tasks. Long-term surviving NPC were found in 7 out of 11 disomic brains and 4 out of 5 trisomic brains, with an average survival rate of 3.1% and 5.9% respectively. Extracellular tau aggregations were elevated in trisomic mice, but implantation with NPC was associated with significantly fewer aggregations. This was also seen in disomic mice. Saline injections significantly elevated tau presence in both karyotypes. Based on these results, we conclude that the modest effects of a few surviving NPC cannot be distinguished from those induced by the implant procedure. However, the changes prompted by neonatal treatment were detectable in aged animals. Collectively, our data are consistent with the hypothesis that neonatal therapeutic intervention in DS has the potential to exert positive lasting effects in the later stages of life but that NPC or the implantation approach may not be the most effective strategy and alternative stem cell types or delivery systems merit further investigation.