Human Neural Stem Cells Reinforce Hippocampal Synaptic Network and Rescue Cognitive Deficits in a Mouse Model of Alzheimer's Disease

Abstract

SummaryAlzheimer's disease (AD) is characterized by memory impairments in its earliest clinical phase. The synaptic loss and dysfunction leading to failures of synaptic networks in AD brain directly cause cognitive deficits of patient. However, it remains unclear whether the synaptic networks in AD brain could be repaired. In this study, we generated functional human induced neural progenitor/stem cells (iNPCs) that had been transplanted into the hippocampus of immunodeficient wild-type and AD mice. The grafted human iNPCs efficiently differentiated into neurons that displayed long-term survival, progressively acquired mature membrane properties, formed graft-host synaptic connections with mouse neurons and functionally integrated into local synaptic circuits, which eventually reinforced and repaired the neural networks of host hippocampus. Consequently, AD mice with human iNPCs exhibited enhanced synaptic plasticity and improved cognitive abilities. Together, our results suggest that restoring synaptic failures by stem cells might provide new directions for the development of novel treatments for human AD.

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

“…An increase in BDNF levels was also observed in the hippocampus. Furthermore, behavior improvement was observed at around 5 to 6 moth post-transplantation [64]. It is worth noting that the source of NSCs from these two studies are very different, where it is plausible to think that reprogrammed somatic cells will have greater neural differentiation capacity.…”

“…Nonetheless both studies show NSCs have successfully engrafted into the host for at least 5 months. Zhang's study suggests NSCs differentiation triggers beneficial effect including increase in synaptic density, neural cell number, behavior improvement [64] whereas Marsh's fail to terminally differentiate NSCs [63]. This information has complicates the causal link and mechanism between NSCs and behavioural improvement, which are nonetheless closely correlated.…”

Altered Patterns of Functional Connectivity and Causal Connectivity in Salience Subnetwork of Subjective Cognitive Decline and Amnestic Mild Cognitive Impairment

“…Alzheimer disease (AD) is a chronic neurodegenerative disorder presented in elderly individuals with conspicuous decline in cognitive deterioration and lapse of memory (Huang et al, 2019;Wessels et al, 2019;Zhang et al, 2019). As one of the phases between normal aging and dementia, amnestic mild cognitive impairment (aMCI) subjects have a 10-15% possibility of developing into AD per year (Petersen et al, 2002;Yang et al, 2017).…”

Stem Cell Therapies in Alzheimer’s Disease: Applications for Disease Modeling

“…In contrast, rapid differentiation and reconstruction of functional neural circuits were observed after transplantation of reprogrammed NPCs from human mononuclear cells. BDNF levels increased, and improvement in behavior impairment was observed after 5 to 6 months (Zhang et al, 2019). These two studies indicate that, compared with normal NSCs, reprogrammed somatic cells might have greater neural lineage-specific differentiation capacity.…”