Mesenchymal Stem Cell-Derived Exosomes Ameliorate Alzheimer’s Disease Pathology and Improve Cognitive Deficits

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.

Exosomes in Alzheimer’s Disease: From Being Pathological Players to Potential Diagnostics and Therapeutics

“…Chen et al, 2021 illustrated the curative mechanism of MSC-EXOs and proposed a cell-free MSC-EXO-based therapy method for treating AD. Results showed that the MSC-EXO therapeutic approach reduced Aβ expression, cleared brain glucose metabolism, and improved cognitive function and neuronal plasticity [ 55 ].…”

Therapeutic Potential of Human Stem Cell Implantation in Alzheimer’s Disease

“…A study by Lu et al suggested stem cell implantation could reduce amyloid-β 40 and 42 accumulation by a clearance mechanism involving increased IDE and NEP levels [140]. A study by Chen et al showed stem cells prevented the downregulation of BDNF, which further supports the studies by Jones et al, Nakano et al, and Ager et al [138,139,143,162]. Neuronal memory and synaptic plasticity-related genes, such as BDNF, SYP, GluR2, and GRIN2B, have been shown to improve memory.…”

“…Coming full circle, recent studies have reestablished support for the previous view that stem cells can reduce both amyloid-β and tau levels, leading to enhanced cognitive function. Recent studies in the past 5 years from Chen et al, Li et al, Lee et al, McGinley et al, and Lu et al showed that MSC implantation could reduce levels of amyloid-β, leading to improved cognition in mice [ 131 , 138 , 140 , 142 ]. In addition to stem cells modulating BACE1 expression to alter APP processing, Lee et al also showed that stem cell transplantation could inhibit tau phosphorylation.…”

“…Moreover, Chen also showed that MSC-exosomes could improve brain glucose metabolism as measured by [18F] FDG-PET. Abnormal expression of HDAC4 was decreased after the treatment, whereas the expressions of HDAC4 target genes like Homer protein homolog 1, synapsin II, and leucine-rich glioma inactivated 1 were increased, leading to amelioration of learning and memory deficits [ 138 ].…”

“…However, a study by Jones et al [162] showed that stem cells increased synaptic density in the brain via BDNF, rather than directly altering amyloid-β and tau levels. [131,138,140,142]. In addition to stem cells modulating BACE1 expression to alter APP processing, Lee et al also showed that stem cell transplantation could inhibit tau phosphorylation.…”