Peripheral Blood-Derived Microglia-Like Cells Decrease Amyloid-β Burden and Ameliorate Cognitive Impairment in a Mouse Model of Alzheimer’s Disease

Article type: Research Article

Authors: Kuroda, Eriko^a | Takata, Kazuyuki^{b; *} | Nishimura, Kaneyasu^b | Oka, Hikaru^a | Sueyoshi, Mari^a | Aitani, Mayu^a | Kouda, Atsushi^a | Satake, Shiho^b | Shima, Chiaki^b | Toda, Yuki^a | Nakata, Susumu^c | Kitamura, Yoshihisa^{a; d; †} | Ashihara, Eishi^{a; †}

Affiliations: [a] Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, Japan | [b] Division of Integrated Pharmaceutical Sciences, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, Japan | [c] Department of Clinical Oncology, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, Japan | [d] Current address: Laboratory of Pharmacology and Neurobiology, College of Pharmaceutical Sciences, Ritsumeikan University Kusatsu, Shiga 525-8577, 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: [email protected].

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

Abstract: Amyloid-β (Aβ) accumulation in the brain triggers the onset of Alzheimer’s disease (AD), and its prevention and elimination are high priorities for anti-AD therapeutic strategies. Microglia, the resident immune cells in the brain, promote Aβ clearance by phagocytosis. Previously, we demonstrated that injection of primary cultured rat microglia and mouse bone marrow-derived microglia-like cells into the brain decreases the level of Aβ and that intrahippocampal injection of these cells ameliorates cognitive impairment in a mouse model of AD. To advance this cell therapeutic strategy to the clinical stage, less invasive ways of preparing autologous microglia-like cells from elderly patients are required. In this study, we demonstrated that hematopoietic stem cells mobilized from the bone marrow to peripheral blood by administering granulocyte colony-stimulating factor and a CXCR4 antagonist to mice differentiated into microglia-like cells upon stimulation with colony-stimulating factor 1 and interleukin-34. The peripheral blood-derived microglia-like (PBDML) cells expressed microglial markers and engaged in Aβ phagocytosis. Although PBDML cells were in an anti-inflammatory state under nonstimulated conditions, they expressed mRNAs encoding proinflammatory cytokines following lipopolysaccharide treatment. PBDML cells injected into the hippocampi of a mouse AD model survived for at least 36 days while phagocytosing Aβ, contributed to a reduction in brain Aβ burden, and ameliorated cognitive impairment in the mice. These results strongly suggest that PBDML cells are a promising source for the development of a novel cell therapy against AD.

Keywords: Alzheimer’s disease, amyloid-β , cell therapy, cognitive impairment, intrahippocampal injection, microglia, Morris water maze, novel object recognition test, peripheral blood, stereology

DOI: 10.3233/JAD-190974

Journal: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 413-429, 2020