title: Therapeutic effects of glatiramer acetate and grafted CD115⁺ monocytes in a mouse model of Alzheimer's disease.
abstract: Weekly glatiramer acetate immunization of transgenic mice modelling Alzheimer's disease resulted in retained cognition (Morris water maze test), decreased amyloid-β plaque burden, and regulation of local inflammation through a mechanism involving enhanced recruitment of monocytes. Ablation of bone marrow-derived myeloid cells exacerbated plaque pathology, whereas weekly administration of glatiramer acetate enhanced cerebral recruitment of innate immune cells, which dampened the pathology. Here, we assessed the therapeutic potential of grafted CD115(+) monocytes, injected once monthly into the peripheral blood of transgenic APPSWE/PS1ΔE9 Alzheimer's disease mouse models, with and without weekly immunization of glatiramer acetate, as compared to glatiramer acetate alone. All immune-modulation treatment groups were compared with age-matched phosphate-buffered saline-injected control transgenic and untreated non-transgenic mouse groups. Two independent cohorts of mice were assessed for behavioural performance (6-8 mice/group); treatments started in 10-month-old symptomatic mice and spanned a total of 2 months. For all three treatments, our data suggest a substantial decrease in cognitive deficit as assessed by the Barnes maze test (P < 0.0001-0.001). Improved cognitive function was associated with synaptic preservation and reduction in cerebral amyloid-β protein levels and astrogliosis (P < 0.001 and P < 0.0001), with no apparent additive effects for the combined treatment. The peripherally grafted, green fluorescent protein-labelled and endogenous monocytes, homed to cerebral amyloid plaques and directly engulfed amyloid-β; their recruitment was further enhanced by glatiramer acetate. In glatiramer acetate-immunized mice and, moreover, in the combined treatment group, monocyte recruitment to the brain was coupled with greater elevation of the regulatory cytokine IL10 surrounding amyloid-β plaques. All treated transgenic mice had increased cerebral levels of MMP9 protein (P < 0.05), an enzyme capable of degrading amyloid-β, which was highly expressed by the infiltrating monocytes. In vitro studies using primary cultures of bone marrow monocyte-derived macrophages, demonstrated that glatiramer acetate enhanced the ability of macrophages to phagocytose preformed fibrillar amyloid-β1-42 (P < 0.0001). These glatiramer acetate-treated macrophages exhibited increased expression of the scavenger receptors CD36 and SCARA1 (encoded by MSR1), which can facilitate amyloid-β phagocytosis, and the amyloid-β-degrading enzyme MMP9 (P < 0.0001-0.001). Overall, our studies indicate that increased cerebral infiltration of monocytes, either by enrichment of their levels in the circulation or by weekly immunization with glatiramer acetate, resulted in substantial attenuation of disease progression in murine Alzheimer's models by mechanisms that involved enhanced cellular uptake and enzymatic degradation of toxic amyloid-β as well as regulation of brain inflammation.
authors.affiliation: 1 Department of Neurosurgery, Maxine-Dunitz Neurosurgical Institute, Cedars-Sinai Medical Centre, Los Angeles, CA 90048, USA.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Koronyo
authors.affiliation: 1 Department of Neurosurgery, Maxine-Dunitz Neurosurgical Institute, Cedars-Sinai Medical Centre, Los Angeles, CA 90048, USA 2 F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Centre, Los Angeles, CA 90048, USA.
authors.forename: Brenda C
authors.initials: BC
authors.lastname: Salumbides
authors.affiliation: 1 Department of Neurosurgery, Maxine-Dunitz Neurosurgical Institute, Cedars-Sinai Medical Centre, Los Angeles, CA 90048, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Sheyn
authors.affiliation: 1 Department of Neurosurgery, Maxine-Dunitz Neurosurgical Institute, Cedars-Sinai Medical Centre, Los Angeles, CA 90048, USA.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Pelissier
authors.affiliation: 1 Department of Neurosurgery, Maxine-Dunitz Neurosurgical Institute, Cedars-Sinai Medical Centre, Los Angeles, CA 90048, USA.
authors.forename: Songlin
authors.initials: S
authors.lastname: Li
authors.affiliation: 1 Department of Neurosurgery, Maxine-Dunitz Neurosurgical Institute, Cedars-Sinai Medical Centre, Los Angeles, CA 90048, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ljubimov
authors.affiliation: 1 Department of Neurosurgery, Maxine-Dunitz Neurosurgical Institute, Cedars-Sinai Medical Centre, Los Angeles, CA 90048, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Moyseyev
authors.affiliation: 1 Department of Neurosurgery, Maxine-Dunitz Neurosurgical Institute, Cedars-Sinai Medical Centre, Los Angeles, CA 90048, USA.
authors.forename: David
authors.initials: D
authors.lastname: Daley
authors.affiliation: 1 Department of Neurosurgery, Maxine-Dunitz Neurosurgical Institute, Cedars-Sinai Medical Centre, Los Angeles, CA 90048, USA.
authors.forename: Dieu-Trang
authors.initials: DT
authors.lastname: Fuchs
authors.affiliation: 1 Department of Neurosurgery, Maxine-Dunitz Neurosurgical Institute, Cedars-Sinai Medical Centre, Los Angeles, CA 90048, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Pham
authors.affiliation: 1 Department of Neurosurgery, Maxine-Dunitz Neurosurgical Institute, Cedars-Sinai Medical Centre, Los Angeles, CA 90048, USA.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Black
authors.affiliation: 1 Department of Neurosurgery, Maxine-Dunitz Neurosurgical Institute, Cedars-Sinai Medical Centre, Los Angeles, CA 90048, USA.
authors.forename: Altan
authors.initials: A
authors.lastname: Rentsendorj
authors.affiliation: 1 Department of Neurosurgery, Maxine-Dunitz Neurosurgical Institute, Cedars-Sinai Medical Centre, Los Angeles, CA 90048, USA 3 Department of Biomedical Sciences, Cedars-Sinai Medical Centre, Los Angeles, CA 90048, USA koronyom@cshs.org.
authors.forename: Maya
authors.initials: M
authors.lastname: Koronyo-Hamaoui
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016186:Receptor, Macrophage Colony-Stimulating Factor
keywords: Alzheimer’s disease; behavioural neurology; dementia; neuroinflammation; neuroprotection