Brain-derived neurotrophic factor modified human umbilical cord mesenchymal stem cells-derived cholinergic-like neurons improve spatial learning and memory ability in Alzheimer's disease rats

Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative disease and the most common type of dementia. Although it is still incurable, stem cell replacement therapy provides new hope for AD. Human umbilical cord mesenchymal stem cells (hUC-MSCs) have multiple differentiation potentials, which can differentiate into cholinergic-like neurons and promote the release of acetylcholine. Brain-derived neurotrophic factor (BDNF) can also promote neurogenesis and synaptic formation, reduce oxidative stress and cell death. Therefore, we investigated the therapeutic effects of BDNF modified hUC-MSCs-derived cholinergic-like neurons in AD rats in this study. To make AD models, 1 μl beta amyloid (Aβ)_1-42 was injected into the right hippocampus of the rats. After two weeks, the hUC-MSCs-derived cholinergic-like neurons null cells or overexpressing BDNF cells delivered by lentiviralvectors were slowly injected into the right hippocampus of the AD rats. After 8 weeks of transplantation, Morris water maze test, Western blotting, Immunohistochemistry, Immunofluorescence assay and TdT mediated dUTP Nick End Labeling (TUNEL) detection were performed. Transplantation of BDNF modified hUC-MSCs-derived cholinergic-like neurons significantly improved spatial learning and memory abilities in the AD rats, increased the release of acetylcholine and ChAT expression in the hippocampus, enhanced the activation of astrocytes and microglia, reduced the expression of Aβ and recombinant human beta-site APP-cleaving enzyme1 (BACE1), inhibited neuronal apoptosis, and promoted neurogenesis. Our results demonstrate that BDNF modified hUC-MSCs-derived cholinergic-like neurons might be a promising therapeutic strategy for AD.

Keywords: Alzheimer’s disease; Brain-derived neurotrophic factor; Cholinergic-like neuron; Human umbilical cord mesenchymal stem cell.