Abstract
Neurodegenerative diseases are devastating medical conditions with no effective treatments. Restoration of impaired neurogenesis represents a promising therapeutic strategy for neurodegenerative diseases. Milk fat globule-epidermal growth factor-factor VIII (MFG-E8) is a secretory glycoprotein that plays a wide range of cellular functions including phagocytosis of apoptotic cells, anti-inflammation, tissue regeneration, and homeostasis. The beneficial role of MFG-E8 has been shown in cerebral ischemia (stroke), neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, and traumatic brain injury. In stroke, MFG-E8 promotes neural stem cell proliferation and their migration toward the ischemic brain tissues. These novel functions of MFG-E8 are primarily mediated through its receptor αvβ3-integrin. Here, we focus on the pivotal role of MFG-E8 in protecting against neuronal diseases by promoting neurogenesis. We also discuss the mechanisms of MFG-E8-mediated neural stem/progenitor cell (NSPC) proliferation and migration, and the potential of MFG-E8 for neural stem cell niche maintenance via angiogenesis. We propose further investigation of the molecular pathways for MFG-E8 signaling in NSPC and effective strategies for MFG-E8 delivery across the blood–brain barrier, which will help develop MFG-E8 as a future drug candidate for the bedside management of neurodegenerative diseases.
Highlights
Neurodegenerative diseases are a heterogeneous group of brain disorders of multifactorial etiologies characterized by the loss of existing neurons and alterations in neuronal replacement via neurogenesis (De Pablo-Fernández et al, 2019; Zetterberg and Schott, 2019)
The proliferation of neural stem cells is not affected in Huntington disease but there is impaired maturation of neurons in the striatum (Phillips et al, 2005; Winner and Winkler, 2015)
Recombinant murine MFG-E8 stimulated the proliferation of mouse embryonic neural stem cells via upregulation of cyclin D2 and downregulation of p53, through αvβ3-integrin signaling (Cheyuo et al, 2015)
Summary
Neurodegenerative diseases are a heterogeneous group of brain disorders of multifactorial etiologies characterized by the loss of existing neurons and alterations in neuronal replacement via neurogenesis (De Pablo-Fernández et al, 2019; Zetterberg and Schott, 2019). The proliferation of neural stem cells is not affected in Huntington disease but there is impaired maturation of neurons in the striatum (Phillips et al, 2005; Winner and Winkler, 2015) Schizophrenia is another common neurodegenerative disorder characterized clinically by delusions, hallucinations, thought disorder, and movement disorder. The cause of hemorrhage was revealed to be defective associations between cerebral microvessels and the surrounding brain parenchyma, composed of neuroepithelial cells, glia, and neuronal precursors These mice developed disorganized neuroepithelial processes in their ganglionic eminences. The above studies have demonstrated the pivotal role of the MFG-E8 receptor, αvβ integrin, in NSPC expansion and maintenance of the associations between cerebral micro-vessels and the surrounding brain parenchyma. The specific aspects of the complex αvβ3-Integrinmediated signal transduction pathway activated by MFG-E8 are discussed in the later part of the review
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