Bone-Marrow-Derived Microglia-Like Cells Ameliorate Brain Amyloid Pathology and Cognitive Impairment in a Mouse Model of Alzheimer’s Disease

Article type: Research Article

Authors: Kawanishi, Shohei^a | Takata, Kazuyuki^{a; d; *} | Itezono, Shouma^a | Nagayama, Hiroko^a | Konoya, Sayaka^a | Chisaki, Yugo^b | Toda, Yuki^a | Nakata, Susumu^c | Yano, Yoshitaka^b | Kitamura, Yoshihisa^{a; e; 1} | Ashihara, Eishi^{a; 1}

Affiliations: [a] Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, Japan | [b] Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, Japan | [c] Department of Clinical Oncology, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, Japan | [d] Current address: Division of Integrated Pharmaceutical Sciences, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, Japan | [e] Laboratory of Pharmacology and Neurobiology, College of Pharmaceutical Sciences, Ritsumeikan University Kusatsu, Shiga, Japan

Correspondence: [*] Correspondence to: Kazuyuki Takata, PhD, Division of Integrated Pharmaceutical Sciences, Kyoto Pharmaceutical University 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan. Tel.: +81 75 595 4632; Fax: +81 75 595 4643; E-mail: kaz@mb. kyoto-phu.ac.jp.

Note: [1 ] These authors both served as senior authors.

Abstract: Microglia, the primary immune cells in the brain, sense pathogens and tissue damage, stimulate cytokine production, and phagocytosis to maintain homeostasis. Accumulation of amyloid-β peptides (Aβ) in the brain triggers the onset of Alzheimer’s disease (AD). Accordingly, promotion of Aβ clearance represents a promising strategy for AD therapy. We previously demonstrated that primary-cultured rat microglia phagocytose Aβ, and that transplantation of these cells ameliorates the Aβ burden in brains of Aβ-injected rats. In this study, we demonstrate that stimulation with colony-stimulating factor-1 efficiently differentiates mouse bone marrow cells into bone marrow-derived microglia-like (BMDML) cells that express markers for microglia, including the recently identified transmembrane protein 119. BMDML cells effectively phagocytose Aβ in vitro, with effects comparable to primary-cultured mouse microglia and greater than peritoneal macrophages. RT-qPCR analysis for cytokine mRNA levels revealed that BMDML cells polarize to a relatively anti-inflammatory state under non-stimulated and inflammatory conditions but exert a pro-inflammatory reaction after lipopolysaccharide treatment. Moreover, BMDML cells hippocampally injected into a mouse model of AD are morphologically similar to the ramified and amoeboid types of residential microglia. Comparisons with simulations assuming a uniform distribution of cells suggest that BMDML cells migrate directionally toward Aβ plaques. We also detected Aβ phagocytosis by BMDML cells, concomitant with a reduction in the number and area of Aβ plaques. Finally, we observed amelioration of cognitive impairment in a mouse model of AD after hippocampal injection of BMDML cells. Our results suggest that BMDML cells have potential as a cell-based disease-modifying therapy against AD.

Keywords: Alzheimer’s disease, amyloid-β, bone-marrow-derived cells, microglia

DOI: 10.3233/JAD-170994

Journal: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 563-585, 2018