Abstract
The accumulation of extracellular β-amyloid (Aβ) plaques within the brain is unique to Alzheimer’s disease (AD) and thought to induce synaptic deficits and neuronal loss. Optimal therapies should tackle the core AD pathophysiology and prevent the decline in memory and cognitive functions. This study aimed to evaluate the therapeutic performance of mesenchymal stem cell-derived exosomes (MSC-exosomes), which are secreted membranous elements encapsulating a variety of MSC factors, on AD. A human neural cell culture model with familial AD (FAD) mutations was established and co-cultured with purified MSC-exosomes. 2-[18F]Fluoro-2-deoxy-d-glucose ([18F]FDG) and novel object recognition (NOR) testing were performed before/after treatment to evaluate the therapeutic effect in vivo. The AD-related pathology and the expression of neuronal memory/synaptic plasticity-related genes were also evaluated. The results showed that MSC-exosomes reduced Aβ expression and restored the expression of neuronal memory/synaptic plasticity-related genes in the cell model. [18F]FDG-PET imaging and cognitive assessment revealed a significant improvement in brain glucose metabolism and cognitive function in AD transgenic mice. The phase of neurons and astrocytes in the brain of AD mice were also found to be regulated after treatment with MSC-exosomes. Our study demonstrates the therapeutic mechanism of MSC-exosomes and provides an alternative therapeutic strategy based on cell-free MSC-exosomes for the treatment of AD.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that accounts for 50–70% of the cases of dementia [1]
Our study demonstrated that coculturing of familial AD (FAD) neural cells with mesenchymal stem cells (MSCs)-exosomes reduced the level of Aβ and prevented the downregulation of memory/synaptic plasticity-related genes
We demonstrated that exosomes derived from Wharton’s jelly MSCs improved AD pathology, downregulated histone deacetylase 4 (HDAC4), and regulated cellular phases simultaneously
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that accounts for 50–70% of the cases of dementia [1]. Clinical symptoms of AD include cognitive decline, shortterm memory failure, orientation problems, and motor abnormalities [2,3]. FDA has approved only five medications for AD, including three cholinesterase inhibitors, one N-methyl-d-aspartate (NMDA) receptor antagonist, and a combination that targets the cholinergic and glutamatergic systems simultaneously [12]. These drugs may alleviate the symptoms of AD but do not slow down the progression of the disease. It is suggested that therapeutic targets for AD should include multiple strategies or combinational remedies for the maximum effectiveness
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