Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory impairments, which has no effective therapy. Stem cell transplantation shows great potential in the therapy of various disease. However, the application of stem cell therapy in neurological disorders, especially the ones with a long-term disease course such as AD, is limited by the delivery approach due to the presence of the brain blood barrier. So far, the most commonly used delivery approach in the therapy of neurological disorders with stem cells in preclinical and clinical studies are intracranial injection and intrathecal injection, both of which are invasive. In the present study, we use repetitive intranasal delivery of human neural stem cells (hNSCs) to the brains of APP/PS1 transgenic mice to investigate the effect of hNSCs on the pathology of AD. The results indicate that the intranasally transplanted hNSCs survive and exhibit extensive migration and higher neuronal differentiation, with a relatively limited glial differentiation. A proportion of intranasally transplanted hNSCs differentiate to cholinergic neurons, which rescue cholinergic dysfunction in APP/PS1 mice. In addition, intranasal transplantation of hNSCs attenuates β-amyloid accumulation by upregulating the expression of β-amyloid degrading enzymes, insulin-degrading enzymes, and neprilysin. Moreover, intranasal transplantation of hNSCs ameliorates other AD-like pathology including neuroinflammation, cholinergic dysfunction, and pericytic and synaptic loss, while enhancing adult hippocampal neurogenesis, eventually rescuing the cognitive deficits of APP/PS1 transgenic mice. Thus, our findings highlight that intranasal transplantation of hNSCs benefits cognition through multiple mechanisms, and exhibit the great potential of intranasal administration of stem cells as a non-invasive therapeutic strategy for AD.
Highlights
Alzheimer’s disease (AD) is a common progressive neurodegenerative disease, which is clinically manifested as memory loss, speaking and problem-solving difficulties, and other cognitive impairments
We firstly examined the property of human neural stem cells (hNSCs) before transplantation. hNSCs were successfully propagated and formed neurospheres when being suspension-cultured for 12 d, indicating that hNSCs have a self-renewal ability (Figure 1A)
We examined the effect of intranasal transplantation of hNSCs on the cognition of amyloid precursor protein (APP)/PS1 transgenic mice. hNSCs were transplanted intranasally to 3.5-month-old APP/PS1 transgenic mice a total of four times at a frequency of once a week, and a behavioral assessment was performed at 6.5 months when the APP/PS1 mice started to exhibit cognitive deficits (Figure 9A)
Summary
Alzheimer’s disease (AD) is a common progressive neurodegenerative disease, which is clinically manifested as memory loss, speaking and problem-solving difficulties, and other cognitive impairments. Aβ is believed to be the instigator of the whole AD event, which leads to neurofibrillary tangles, synapse loss, neuroinflammation, neuronal death, and cognitive deficits (Long and Holtzman, 2019). All current clinical trials targeting Aβ, tau, and even neuroinflammation have failed so far (Long and Holtzman, 2019). Current drugs, such as acetylcholinesterase inhibitors or N-methyl-D-aspartic acid receptor antagonists, are only beneficial for AD symptoms. A new multi-targets drug, GV-971, was conditionally approved for sale in China but only used for the treatment of mild to moderate AD (Wang et al, 2019). Finding more strategies for AD therapy is of great importance
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