Effect of growth differentiation factor-15 secreted by human umbilical cord blood-derived mesenchymal stem cells on amyloid beta levels in in vitro and in vivo models of Alzheimer's disease

Alzheimer's disease (AD), which is the most common progressive neurodegenerative disease, causes learning and memory impairment. The pathological progress of AD can derive from imbalanced homeostasis of amyloid beta (Aβ) in the brain. In such cases, microglia play important roles in regulating the brain Aβ levels. In the present study, we found that human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) can increase, through paracrine action, the ability of microglial cells to clear Aβ. In order to identify the associated paracrine factors, a secretome of hUCB-MSCs co-cultured with Aβ-treated BV2 microglial cells was analyzed using a human cytokine protein array. As a result, growth differentiation factor-15 (GDF-15) was identified as a predominant candidate, and its association with Aβ clearance by microglial cells was investigated in vitro and in a 5XFAD mouse model. When Aβ-treated BV2 cells were treated with exogenous recombinant GDF-15, the Aβ levels in the culture medium decreased. Moreover, GDF-15 injection in the brain parenchyma of 5XFAD mice also led to decrease in Aβ plaques. In contrast, co-culture of BV2 cells and hUCB-MSCs treated with GDF-15-specific siRNA did not influence the Aβ levels in the culture medium. To elucidate how these phenomena are related, we confirmed that GDF-15 specifically increases insulin-degrading enzyme (IDE) expression in microglial cells through TGFβ receptor type II (TGFβRII), both in vitro and in vivo. These findings suggest that hUCB-MSCs promote the Aβ clearance ability of microglial cells through regulation of GDF-15 secretion, thus elucidating a therapeutic mechanism for AD.