| First Author | Koronyo-Hamaoui M | Year | 2020 |
| Journal | Brain | Volume | 143 |
| Issue | 1 | Pages | 336-358 |
| PubMed ID | 31794021 | Mgi Jnum | J:284850 |
| Mgi Id | MGI:6391985 | Doi | 10.1093/brain/awz364 |
| Citation | Koronyo-Hamaoui M, et al. (2020) Peripherally derived angiotensin converting enzyme-enhanced macrophages alleviate Alzheimer-related disease. Brain 143(1):336-358 |
| abstractText | Targeted overexpression of angiotensin-converting enzyme (ACE), an amyloid-beta protein degrading enzyme, to brain resident microglia and peripheral myelomonocytes (ACE10 model) substantially diminished Alzheimer's-like disease in double-transgenic APPSWE/PS1DeltaE9 (AD+) mice. 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-beta1-42 fibrils and oligomers. The combined in vivo approaches showed that increased cerebral infiltration of ACE10 as compared to wild-type monocytes ( approximately 3-fold increase; P < 0.05) led to reductions in cerebral soluble amyloid-beta1-42, vascular and parenchymal amyloid-beta deposits, and astrocytosis (31%, 47-80%, and 33%, respectively; P < 0.05-0.0001). ACE10 macrophages surrounded brain and retinal amyloid-beta plaques and expressed 3.2-fold higher insulin-like growth factor-1 (P < 0.01) and approximately 60% lower tumour necrosis factor-alpha (P < 0.05). Importantly, blood enrichment with CD115+-ACE10 monocytes in symptomatic AD+ mice resulted in pronounced synaptic and cognitive preservation (P < 0.05-0.001). In vitro analysis of macrophage response to well-defined amyloid-beta1-42 conformers (fibrils, prion rod-like structures, and stabilized soluble oligomers) revealed extensive resistance to amyloid-beta1-42 species by ACE10 macrophages. They exhibited 2-5-fold increased surface binding to amyloid-beta conformers as well as substantially more effective amyloid-beta1-42 uptake, at least 8-fold higher than those of wild-type macrophages (P < 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 < 0.05-0.0001), endosomal processing (P < 0.05-0.0001), and approximately 80% increased extracellular degradation of amyloid-beta1-42 (P < 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-alpha), pro-healing immune profiles (high insulin-like growth factor-1, elongated cell morphology), even following exposure to Alzheimer's-related amyloid-beta1-42 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-beta forms. |
