Gain of BDNF Function in Engrafted Neural Stem Cells Promotes the Therapeutic Potential for Alzheimer’s Disease

Abstract

Stem cell-based therapy is a potential treatment for neurodegenerative diseases, but its application to Alzheimer’s disease (AD) remains limited. Brain-derived neurotrophic factor (BDNF) is critical in the pathogenesis and treatment of AD. Here, we present a novel therapeutic approach for AD treatment using BDNF-overexpressing neural stem cells (BDNF-NSCs). In vitro, BDNF overexpression was neuroprotective to beta-amyloid-treated NSCs. In vivo, engrafted BDNF-NSCs-derived neurons not only displayed the Ca2+-response fluctuations, exhibited electrophysiological properties of mature neurons and integrated into local brain circuits, but recovered the cognitive deficits. Furthermore, BDNF overexpression improved the engrafted cells’ viability, neuronal fate, neurite complexity, maturation of electrical property and the synaptic density. In contrast, knockdown of the BDNF in BDNF-NSCs diminished stem cell-based therapeutic efficacy. Together, our findings indicate BDNF overexpression improves the therapeutic potential of engrafted NSCs for AD via neurogenic effects and neuronal replacement, and further support the feasibility of NSC-based ex vivo gene therapy for AD.

The Seed of <i>Zizyphus jujuba</i> var. <i>spinosa</i> Attenuates Alzheimer’s Disease-Associated Hippocampal Synaptic Deficits through BDNF/TrkB Signaling

“…Thus, the absence of BDNF action might be responsible for AD symptoms, including neuronal dysfunctions. 10,29,30) Previous reports have shown that a direct 31) or indirect 32) increase of BDNF levels reduces ADlike symptoms.…”

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

“…After transplantation, NSCs differentiate into neurons and/or glial cells and release trophic factors. Asymmetric NSC division generates different cell types that replace damaged neurons [29,30] and the neurotrophic factors released from both differentiated cells and stem cells are related to rapid differentiation [31] and play a significant role in neuroprotection to rescue synaptic density [32][33][34]. Secretion of neurotrophic factors and cell restoration has been shown to improve individual memory function [35,36].…”

“…Novel drugs that are currently in development have shifted their focus to targeting these mechanisms to halt or reverse disease progression [38]. Considering that NSCs can restore damaged cells, reduce Aβ aggregation, ameliorate AD pathology as well as restoring neuronal cell populations [32,34,39], NSC therapy is a promising and flexible novel therapeutic strategy for targeting the primary cause of AD. Unfortunately the efficacy compared with placebo groups has been inconsistent, not to mention several ethical questions and disagreements on how they should be correctly handled [40].…”

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

“…Interestingly, the transplantation of human NGFexpressing NSCs (genetically modified) ameliorated cognitive function in AD mice (Lee et al 2012a). In addition, transplantation of BDNF-overexpressing NSCs improved synaptic density and restored memory formation (Wu et al 2016). On the other side, transplantation of genetically modified NSCs that express neprilysin (NEP), the Aβ-degrading enzyme, into the hippocampi of AD transgenic (Tg) mice, reduced Aβ pathology and improved synaptic plasticity and function (Blurton-Jones et al 2014).…”