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 (A beta) in the brain. In such cases, microglia play important roles in regulating the brain A beta 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 A beta. In order to identify the associated paracrine factors, a secretome of hUCB-MSCs co-cultured with A beta-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 A beta clearance by microglial cells was investigated in vitro and in a 5XFAD mouse model. When A beta-treated BV2 cells were treated with exogenous recombinant GDF-15, the A beta levels in the culture medium decreased. Moreover, GDF-15 injection in the brain parenchyma of 5XFAD mice also led to decrease in A beta plaques. In contrast, co-culture of BV2 cells and hUCB-MSCs treated with GDF-15-specific siRNA did not influence the A beta 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 TGF beta receptor type II (TGF beta RII), both in vitro and in vivo. These findings suggest that hUCB-MSC5 promote the A beta clearance ability of microglial cells through regulation of GDF-15 secretion, thus elucidating a therapeutic mechanism for AD. (C) 2018 Elsevier Inc. All rights reserved.