Human Neural Stem Cell Transplantation Rescues Cognitive Defects in APP/PS1 Model of Alzheimer’s Disease by Enhancing Neuronal Connectivity and Metabolic Activity

Abstract

Alzheimer’s disease (AD), the most frequent type of dementia, is featured by Aβ pathology, neural degeneration and cognitive decline. To date, there is no cure for this disease. Neural stem cell (NSC) transplantation provides new promise for treating AD. Many studies report that intra-hippocampal transplantation of murine NSCs improved cognition in rodents with AD by alleviating neurodegeneration via neuronal complement or replacement. However, few reports examined the potential of human NSC transplantation for AD. In this study, we implanted human brain-derived NSCs (hNSCs) into bilateral hippocampus of an amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (Tg) mouse model of AD to test the effects of hNSC transplantation on Alzheimer’s behavior and neuropathology. Six weeks later, transplanted hNSCs engrafted into the brains of AD mice, migrated dispersedly in broad brain regions, and some of them differentiated into neural cell types of central nervous system (CNS). The hNSC transplantation restored the recognition, learning and memory deficits but not anxiety tasks in AD mice. Although Aβ plaques were not significantly reduced, the neuronal, synaptic and nerve fiber density was significantly increased in the frontal cortex and hippocampus of hNSC-treated AD mice, suggesting of improved neuronal connectivity in AD brains after hNSC transplantation. Ultrastructural analysis confirmed that synapses and nerve fibers maintained relatively well-structured shapes in these mice. Furthermore, in vivo magnetic resonance spectroscopy (MRS) showed that hNSC-treated mice had notably increased levels of N-acetylaspartate (NAA) and Glu in the frontal cortex and hippocampus, suggesting that neuronal metabolic activity was improved in AD brains after hNSC transplantation. These results suggest that transplanted hNSCs rescued Alzheimer’s cognition by enhancing neuronal connectivity and metabolic activity through a compensation mechanism in APP/PS1 mice. This study provides preclinical evidence that hNSC transplantation can be a possible and feasible strategy for treating patients with AD.

Ultrasound Mediated Microbubbles Destruction Assists Dual Delivery of Beta-amyloid Antibody and NSCs to Restore Neural Function in Transgenic Mice of Alzheimer’s Disease

“…An up-regulation of BDNF was demonstrated in our result, however, there were no significant improvement in SYN with the same methods between the combined delivery group and the single Aβ antibody delivery group, even though following a consecutive four times treatment. SYN was significantly reduced in relation to the deposition of Aβ plaques in the hippocampus and cortex in AD, leading to the loss of synapses and dysfunction of synaptic transmission [25][26][27]. According to our results, Aβ clearance has been improved in the dual delivery approach, while SYN remained nearly no recover.…”

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

“…Similar behavioural improvement is achieved after endogenous neurogenesis, which is enhanced after hNSC transplantation in Tg2576 mice [50]. Likewise, in APP/PS1 Tg mice, synaptic density and cognitive impairment were significantly improved, and neural metabolism was also ameliorated, suggesting that NSCs may alter neuronal metabolic activity [53]. This was not mentioned in the 3xTg and Tg2576 models.…”

“…This inserted human gene produces more Aβ than murine APP. Both Aβ 42 and Aβ 40 levels [53]. In 2018, a study by McGinley suggested that transplanted hNSCs regulate microglial activation and thus reduces Aβ levels.…”

“…Some partially contradicting results have been obtained. In one study, hNSCs rescued cognitive deficits without altering synaptic density [54], while in another, hNSCs improved synaptic density and neural metabolic activity, but mitigated behavioural improvement [53]. In some studies, hNSC transplantation activated microglia and decreased Aβ level [54], while a review of mNSC studies found no change in Aβ levels, although cognitive deficits were rescued.…”

The Interaction of EphA4 With PDGFRβ Regulates Proliferation and Neuronal Differentiation of Neural Progenitor Cells in vitro and Promotes Neurogenesis in vivo

“…Aβ deposits in the hippocampus could be detected in 8-month-old Tg mice (Supplementary Figure S2). Genotype was confirmed by PCR of mouse tail tissue, as previously described (Li et al, 2016). All animal experiments were carried out in accordance with the guidelines of the Liaocheng People's Hospital (Shandong, China) and were approved by the Ethics Committee of Liaocheng People's Hospital (nos.…”