Microglia‐targeted stem cell therapies for Alzheimer disease: A preclinical data review

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Although tremendous advances have been witnessed in the pathophysiological study of Alzheimer disease (AD) (Sperling et al., 2011), there are still no effective treatments to curb or prevent the disease; current treatments merely focus on relieving the AD‐associated symptoms. This could be due to a lack of understanding of the mechanisms implicated in AD pathogenesis (Li, Bao, & Wang, 2016). To identify more effective treatment strategies, a complete understanding of AD pathophysiology is required. Past decades of AD research have stressed the amyloid hypothesis; however, it has been gradually established that microglia play a vital role in the pathogenesis and progression of AD. Physiologically, microglia are important in immune defense and are assumed to play critical roles in maintaining brain homeostasis. Such homeostatic function is partly achieved through the broad interactions and quick responses of microglia in changing brain microenvironments (Davalos et al., 2005; Nimmerjahn, Kirchhoff, & Helmchen, 2005). In response to Aβ and tau pathology, microglial morphologies and functions change dramatically. With advancing AD pathology, these microglial adaptations are in conflict with their protective roles in the brain, leading to synaptic instability and consequent cognitive decline (Udeochu, Shea, & Villeda, 2016).
In past decades, stem cell therapies have attracted attention for the promise of their undoing damage to the central nervous system (CNS). Transplanted cells have the potential to increase the survival and function of endogenous microglia (Martino & Pluchino, 2006). Stem cell grafts could provide neuroprotective effects by secreting molecules with immunomodulatory properties and tissue trophic functions, such as nerve growth factor (NGF) and brain‐derived neurotrophic factor (BDNF). In addition, stem cells could release microvesicles, which may contain mRNA, regulatory miRNA, and intact organelles (Ratajczak et al., 2012). Following stem cell transplantation, the microglial phenotype varies from a “classically activated” type, which is highly proinflammatory, to an “alternatively activated” type, which is beneficial, less inflammatory, and neuroprotective (Giunti, Parodi, Cordano, Uccelli, & Kerlero, 2014).
In this review, we discuss the changing microglial phenotype in response to AD and transplanted stem cell therapy. In addition, we provide insight into the responses of native microglial cells to grafted stem cells in AD, and the factors influencing these mechanisms.

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