Abstract
Alzheimer's disease (AD) animal studies have reported that mesenchymal stem cells (MSCs) have therapeutic effects; however, clinical trial results are controversial. Neprilysin (NEP) is the main cleavage enzyme of β-amyloid (Aβ), which plays a major role in the pathology and etiology of AD. We evaluated whether transplantation of MSCs with NEP gene modification enhances the therapeutic effects in an AD animal model and then investigated these pathomechanisms. We manufactured NEP gene-enhanced human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and intravenously transplanted them in Aβ1-42-injected AD animal models. We compared the differences in behavioral tests and immunohistochemical assays between four groups: normal, Aβ1-42 injection, naïve hUC-MSCs, and NEP-enhanced hUC-MSCs. Both naïve and NEP-enhanced hUC-MSC groups showed significant improvements in memory compared to the Aβ1-42 injection group. There was no significant difference between naïve and NEP-enhanced hUC-MSC groups. There was a significant decrease in Congo red, BACE-1, GFAP, and Iba-1 and a significant increase in BDNF, NeuN, and NEP in both hUC-MSC groups compared to the Aβ1-42 injection group. Among them, BDNF, NeuN, GFAP, Iba-1, and NEP showed more significant changes in the NEP-enhanced hUC-MSC group than in the naïve group. After stem cell injection, stem cells were not found. Extracellular vesicles (EVs) were equally observed in the hippocampus in the naïve and NEP-enhanced hUC-MSC groups. However, the EVs of NEP-enhanced hUC-MSCs contained higher amounts of NEP as compared to the EVs of naïve hUC-MSCs. Thus, hUC-MSCs affect AD animal models through stem cell-released EVs. Although there was no significant difference in cognitive function between the hUC-MSC groups, NEP-enhanced hUC-MSCs had superior neurogenesis and anti-inflammation properties compared to naïve hUC-MSCs due to increased NEP in the hippocampus by enriched NEP-possessing EVs. NEP gene-modified MSCs that release an increased amount of NEP within EVs may be a promising therapeutic option in AD treatment.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia that induces the deterioration of active daily life
Extracellular vesicles (EVs) of NEP-Enhanced hUC-mesenchymal stem cells (MSCs) Contain Higher NEP Our study demonstrated that both naïve and NEP-enhanced mRNA and Protein Levels than Those of Naïve hUC-MSCs. hUC-MSCs induced the improvement of cognitive function in Aβ1-42-injected mouse AD models, but there was no significant difference between the two groups
We found that the NEP-enhanced hUC-MSC group had increased levels of brain-derived neurotrophic factor (BDNF) and NeuN and decreased levels of glial fibrous acid protein (GFAP) and ionized calcium-binding adapter molecule-1 (Iba-1) compared to naïve hUC-MSCs
Summary
Alzheimer’s disease (AD) is the most common form of dementia that induces the deterioration of active daily life. AD is pathologically characterized by extracellular deposits (senile plaques) of β-amyloid (Aβ) and intracellular neurofibrillary tangles, leading to selective neuronal loss in the diseased brain [1,2,3]. Progressive memory loss and cognitive decline occur as the disease progresses [2,3,4]. The main treatments for AD approved by the FDA include acetylcholinesterase inhibitors and N-methyl D-aspartate receptor antagonists; these drugs do not affect AD pathophysiology, but rather offer temporary symptomatic relief [5,6,7]. Numerous studies have been conducted each year focusing on the development of a disease-modifying treatment of AD, but the results are somewhat unsatisfactory.
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