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In this study, we explored the impact of selective and transient angiotensin-converting enzyme overexpression on macrophage behaviour and the relative contribution of bone marrow-derived ACE10 macrophages, but not microglia, in attenuating disease progression. To this end, two in vivo approaches were applied in AD+ mice: (i) ACE10\/GFP+ bone marrow transplantation with head shielding; and (ii) adoptive transfer of CD115+-ACE10\/GFP+ monocytes to the peripheral blood. Extensive in vitro studies were further undertaken to establish the unique ACE10-macrophage phenotype(s) in response to amyloid-\u03b21-42 fibrils and oligomers. The combined in vivo approaches showed that increased cerebral infiltration of ACE10 as compared to wild-type monocytes (\u223c3-fold increase; P &amp;lt; 0.05) led to reductions in cerebral soluble amyloid-\u03b21-42, vascular and parenchymal amyloid-\u03b2 deposits, and astrocytosis (31%, 47\u201380%, and 33%, respectively; P &amp;lt; 0.05\u20130.0001). ACE10 macrophages surrounded brain and retinal amyloid-\u03b2 plaques and expressed 3.2-fold higher insulin-like growth factor-1 (P &amp;lt; 0.01) and \u223c60% lower tumour necrosis factor-\u03b1 (P &amp;lt; 0.05). Importantly, blood enrichment with CD115+-ACE10 monocytes in symptomatic AD+ mice resulted in pronounced synaptic and cognitive preservation (P &amp;lt; 0.05\u20130.001). In vitro analysis of macrophage response to well-defined amyloid-\u03b21-42 conformers (fibrils, prion rod-like structures, and stabilized soluble oligomers) revealed extensive resistance to amyloid-\u03b21-42 species by ACE10 macrophages. They exhibited 2\u20135-fold increased surface binding to amyloid-\u03b2 conformers as well as substantially more effective amyloid-\u03b21-42 uptake, at least 8-fold higher than those of wild-type macrophages (P &amp;lt; 0.0001), which were associated with enhanced expression of surface scavenger receptors (i.e. CD36, scavenger receptor class A member 1, triggering receptor expressed on myeloid cells 2, CD163; P &amp;lt; 0.05\u20130.0001), endosomal processing (P &amp;lt; 0.05\u20130.0001), and \u223c80% increased extracellular degradation of amyloid-\u03b21-42 (P &amp;lt; 0.001). Beneficial ACE10 phenotype was reversed by the angiotensin-converting enzyme inhibitor (lisinopril) and thus was dependent on angiotensin-converting enzyme catalytic activity. Further, ACE10 macrophages presented distinct anti-inflammatory (low inducible nitric oxide synthase and lower tumour necrosis factor-\u03b1), pro-healing immune profiles (high insulin-like growth factor-1, elongated cell morphology), even following exposure to Alzheimer\u2019s-related amyloid-\u03b21-42 oligomers. Overall, we provide the first evidence for therapeutic roles of angiotensin-converting enzyme-overexpressing macrophages in preserving synapses and cognition, attenuating neuropathology and neuroinflammation, and enhancing resistance to defined pathognomonic amyloid-\u03b2 forms.<\/jats:p>","DOI":"10.1093\/brain\/awz364","type":"journal-article","created":{"date-parts":[[2019,11,8]],"date-time":"2019-11-08T17:21:54Z","timestamp":1573233714000},"page":"336-358","source":"Crossref","is-referenced-by-count":72,"title":["Peripherally derived angiotensin converting enzyme-enhanced macrophages alleviate Alzheimer-related disease"],"prefix":"10.1093","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2864-8442","authenticated-orcid":false,"given":"Maya","family":"Koronyo-Hamaoui","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"name":"Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Sheyn","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric Y","family":"Hayden","sequence":"additional","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine at UCLA, Mary S. Easton Center for Alzheimer\u2019s Disease Research at UCLA, Brain Research Institute, Molecular Biology Institute, University of California, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songlin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"name":"Institute of Neuroscience and Chemistry, and Institute of Life Sciences, Wenzhou University, Wenzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dieu-Trang","family":"Fuchs","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna C","family":"Regis","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dahabada H J","family":"Lopes","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith L","family":"Black","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth E","family":"Bernstein","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2389-3417","authenticated-orcid":false,"given":"David B","family":"Teplow","sequence":"additional","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine at UCLA, Mary S. Easton Center for Alzheimer\u2019s Disease Research at UCLA, Brain Research Institute, Molecular Biology Institute, University of California, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastien","family":"Fuchs","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosef","family":"Koronyo","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Altan","family":"Rentsendorj","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 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