Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease

Abstract

Neural stem cell (NSC) transplantation represents an unexplored approach for treating neurodegenerative disorders associated with cognitive decline such as Alzheimer disease (AD). Here, we used aged triple transgenic mice (3xTg-AD) that express pathogenic forms of amyloid precursor protein, presenilin, and tau to investigate the effect of neural stem cell transplantation on AD-related neuropathology and cognitive dysfunction. Interestingly, despite widespread and established Aß plaque and neurofibrillary tangle pathology, hippocampal neural stem cell transplantation rescues the spatial learning and memory deficits in aged 3xTg-AD mice. Remarkably, cognitive function is improved without altering Aß or tau pathology. Instead, the mechanism underlying the improved cognition involves a robust enhancement of hippocampal synaptic density, mediated by brainderived neurotrophic factor (BDNF). Gain-of-function studies show that recombinant BDNF mimics the beneficial effects of NSC transplantation. Furthermore, loss-of-function studies show that depletion of NSC-derived BDNF fails to improve cognition or restore hippocampal synaptic density. Taken together, our findings demonstrate that neural stem cells can ameliorate complex behavioral deficits associated with widespread Alzheimer disease pathology via BDNF.beta-amyloid ͉ neurotrophin ͉ synapse ͉ tau ͉ memory

Human neural stem cell transplantation into the corpus callosum of Alzheimer's mice

“…This is in line with many reports of stem cell migration via white matter tracts 12, 13, 14. Given that stem cell efficacy is improved when coupled with trophic factor delivery,2, 16, 17, 18 facilitating increased NSC migration could provide enhanced and widespread neurotrophic support to local brain areas. Moreover, targeting the CC provides the largest migratory area for transplanted stem cells, likely more than any other intracranial target, enabling further enrichment throughout the diseased brain environment.…”

“…Cellular therapies represent a potential disease‐modifying treatment for Alzheimer's disease (AD), with multifaceted therapeutic benefits including tissue replacement, secretion of neuroprotective trophic factors, and/or modulation of inflammation 1, 2, 3, 4, 5, 6. As such, transplantation of stem cells from various sources into the hippocampus improves cognitive impairment in murine AD models 1, 7, 8.…”

Human adipose tissue‐derived mesenchymal stem cells improve cognitive function and physical activity in ageing mice

“…Transplantation of stem cells improves cognitive function in AD model animals by enhancing hippocampal synaptic density mediated by BDNF (Xuan et al, 2008;Blurton-Jones et al, 2009). In addition, exogenous NGF rescues cholinergic neurons in the basal forebrain and improves cognitive function in aged animals (Markowska et al, 1994), and NSCs overexpressing NGF restore memory deficits in AD model animals (Lee et al, 2012).…”

“…In contrast to a transient improvement in body function by pharmaceuticals, stem cells may prevent or delay host cell death and restore injured tissues (Lindvall and Kokaia, 2006;Blurton-Jones et al, 2009;Kim and de Vellis, 2009). Mesenchymal stem cells (MSCs) have been isolated from several tissues, such as bone marrow, adipose tissue, umbilical cord blood, and the amniotic membrane (Pittenger et al, 1999;Díaz-Prado et al, 2011).…”

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…In APPxPS1 mouse AD models, there are only limited numbers of new neurons generated and the capacity of the new granule cells is reduced in a sex‐unbalanced manner (Richetin, Petsophonsakul, Roybon, Guiard, & Rampon, 2017). NSC transplantation slowed the disease progression in an AD mouse model (Blurton‐Jones et al, 2009), while directed expression of a transcription factor, Neurod1, in cycling hippocampal progenitors could produce population of highly connected new neurons and restore spatial memory in AD mouse model (Richetin et al, 2015). …”