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The effects of enhancing angiotensin converting enzyme in myelomonocytes on ameliorating Alzheimer’s-related disease and preserving cognition

Danziger, Ron, Fuchs, Dieu-Trang, Koronyo, Yosef, Rentsendorj, Altan, Sheyn, Julia, Hayden, Eric Y., Teplow, David B., Black, Keith L., Fuchs, Sebastien, Bernstein, Kenneth E., Koronyo-Hamaoui, Maya·2023·Frontiers in Physiology
DOI 10.3389/fphys.2023.1179315PMC PMC10326285
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Abstract

This review examines the role of angiotensin-converting enzyme (ACE) in the context of Alzheimer’s disease (AD) and its potential therapeutic value. ACE is known to degrade the neurotoxic 42-residue long alloform of amyloid β-protein (Aβ 42), a peptide strongly associated with AD. Previous studies in mice, demonstrated that targeted overexpression of ACE in CD115+ myelomonocytic cells (ACE10 models) improved their immune responses to effectively reduce viral and bacterial infection, tumor growth, and atherosclerotic plaque. We further demonstrated that introducing ACE10 myelomonocytes (microglia and peripheral monocytes) into the double transgenic APP SWE/PS1 ΔE9 murine model of AD (AD+ mice), diminished neuropathology and enhanced the cognitive functions. These beneficial effects were dependent on ACE catalytic activity and vanished when ACE was pharmacologically blocked. Moreover, we revealed that the therapeutic effects in AD+ mice can be achieved by enhancing ACE expression in bone marrow (BM)-derived CD115+ monocytes alone, without targeting central nervous system (CNS) resident microglia. Following blood enrichment with CD115+ ACE10-monocytes versus wild-type (WT) monocytes, AD+ mice had reduced cerebral vascular and parenchymal Aβ burden, limited microgliosis and astrogliosis, as well as improved synaptic and cognitive preservation. CD115+ ACE10-versus WT-monocyte-derived macrophages (Mo/MΦ) were recruited in higher numbers to the brains of AD+ mice, homing to Aβ plaque lesions and exhibiting a highly Aβ-phagocytic and anti-inflammatory phenotype (reduced TNFα/iNOS and increased MMP-9/IGF-1). Moreover, BM-derived ACE10-Mo/MΦ cultures had enhanced capability to phagocytose Aβ 42 fibrils, prion-rod-like, and soluble oligomeric forms that was associated with elongated cell morphology and expression of surface scavenger receptors (i.e., CD36, Scara-1). This review explores the emerging evidence behind the role of ACE in AD, the neuroprotective properties of monocytes overexpressing ACE and the therapeutic potential for exploiting this natural mechanism for ameliorating AD pathogenesis.

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FIGURE 1 Neuroprotection by ACE-overexpressing monocytes and macrophages in APPSWE/PS1ΔE9 (AD+) mice. (A) Description of the genetic composition for the 3 groups of bone marrow (BM) donor mice at the GFP, APPSWE/PS1ΔE9 (AD+), and ACE loci: GFP−AD+ACEWT, GFP+AD−ACEWT, or GFP+AD−ACE10. In the ACE10 mouse models, ACE expression is controlled by the c-fms (CD115) promoter that substituted the endogenous ACE promoter. This results in the over expression of ACE in monocytes and macrophages (Mo/MΦ). (B) BM transplantation experiments: 2-month-old double transgenic AD+ recipient mice underwent irradiation with head shielding to prevent brain irradiation and inflammation. Their BM was then reconstituted by an intravenous injection of 5 million BM cells from one of the three types of donors. This BM transplantation generated BMAD+ , BMWT, and BMACE10 chimeric AD+ mice. These mice underwent retinal imaging at the age of 7 months, followed by perfusion and harvest of eyes and brains for analysis. (C) A representative live fluorescence image of a BM-chimeric AD+ mouse retina, demonstrating the feasibility to noninvasively detect in vivo infiltrating GFP+ Mo/MΦ in the retina. [(D), left] Fluorescence micrograph of a BMACE10::AD+ chimeric mouse retina (previously in vivo imaged) showing the homing of GFP+/CD45hi ACE10 Mo/MΦ to the site of retinal 4G8+-Aβ deposit. Scale bar = 5 μm. [(D), right] Infiltrating Mo/MΦ (GFP+/CD45hi; arrows) at the 6E10+-Aβ plaque site are also detected in the BMWT::AD+ chimeric mouse brain. Scale bar = 20 μm. (E) Quantitative flow cytometry analysis of cerebral infiltrating GFP+-Mo/MΦ in BMACE10 versus BMWT chimeric AD+ mice. (F) Micrographs of curcumin+-Aβ plaques (yellow) or GFAP+ astrocytes (pink) in the cortices of BMWT versus BMACE10 AD+ chimeric mice. Scale bar = 50 μm. (G) Quantitative immunohistochemical (IHC) analysis of 6E10+-Aβ plaque area in the cortex of BMACE10 versus BMAD+ AD+-chimeric mice. (H) Quantitative IHC analysis of cortical GFAP+ astrocytosis area in AD+-chimeric mice. (I) Representative fluorescent micrographs of cortical brain regions stained against IGF-1 (red) combined with myeloid cell markers, IBA1 (white) and CD45 (green), and nuclei (DAPI, blue) in BMWT versus BMACE10 AD+-chimeric mice. Scale bars = 10 μm. Brain-infiltrating CD45hi IBA1+ ACE10-versus WT-Mo/MΦ highly expressed IGF-1 in AD+-chimeric mice. (J). Quantitative IHC analysis of % IGF-1+ area colocalized with Mo/MΦ in BMWT versus BMACE10 AD+-chimeric mice. (K) Quantitative flow cytometry analysis of TNFα expression levels in infiltrating ACE10-versus WT-MΦ (GFP+ CD11b+ CD45hi Ly6Cint-hi F4/80hi) in chimeric AD+ mice. (L) An additional study involved adoptive transfer of 5-6 million ACE10-or WT-CD115+ monocytes (MoBM) from young donor mice into the peripheral blood of 8-month-old AD+ mice. These inflammatory monocytes were isolated from the BM of GFP+ donor mice and enriched in the tube using the CD115-positive MACS column sorting procedure. ACE10- (MoACE10) or WT- (MoWT) BM were then injected into the tail vein of recipient AD+ mice. At the age of 11 months, mice underwent behavioral testing. (M) Barnes maze cognitive test: average errors count during the reversal phase, days 8 and 9. Statistics: (left) two-way ANOVA and Bonferroni’s post-test; (right) Day 9 memory test by one-way ANOVA and Bonferroni’s post test. (N) Severity of vascular Aβ deposits is defined as CAA score assessed with thioflavin-S (Thio-S+) staining in AD+ mice brain. (O) Quantitative IHC analysis of hippocampal pre-(VGluT1+) and post-(PSD95+) synaptic areas in MoACE10-treated mice compared to age- and gender-matched PBS-injected control AD+ and naïve WT mice. Illustration in panels A, B and L were created with Biorender.com, as well as images and graphs were used as original or modified from (Koronyo-Hamaoui et al., 2020) by permission of Oxford University Press.
FIGURE 1 Neuroprotection by ACE-overexpressing monocytes and macrophages in APPSWE/PS1ΔE9 (AD+) mice. (A) Description of the genetic composition for the 3 groups of bone marrow (BM) donor mice at the GFP, APPSWE/PS1ΔE9 (AD+), and ACE loci: GFP−AD+ACEWT, GFP+AD−ACEWT, or GFP+AD−ACE10. In the ACE10 mouse models, ACE expression is controlled by the c-fms (CD115) promoter that substituted the endogenous ACE promoter. This results in the over expression of ACE in monocytes and macrophages (Mo/MΦ). (B) BM transplantation experiments: 2-month-old double transgenic AD+ recipient mice underwent irradiation with head shielding to prevent brain irradiation and inflammation. Their BM was then reconstituted by an intravenous injection of 5 million BM cells from one of the three types of donors. This BM transplantation generated BMAD+ , BMWT, and BMACE10 chimeric AD+ mice. These mice underwent retinal imaging at the age of 7 months, followed by perfusion and harvest of eyes and brains for analysis. (C) A representative live fluorescence image of a BM-chimeric AD+ mouse retina, demonstrating the feasibility to noninvasively detect in vivo infiltrating GFP+ Mo/MΦ in the retina. [(D), left] Fluorescence micrograph of a BMACE10::AD+ chimeric mouse retina (previously in vivo imaged) showing the homing of GFP+/CD45hi ACE10 Mo/MΦ to the site of retinal 4G8+-Aβ deposit. Scale bar = 5 μm. [(D), right] Infiltrating Mo/MΦ (GFP+/CD45hi; arrows) at the 6E10+-Aβ plaque site are also detected in the BMWT::AD+ chimeric mouse brain. Scale bar = 20 μm. (E) Quantitative flow cytometry analysis of cerebral infiltrating GFP+-Mo/MΦ in BMACE10 versus BMWT chimeric AD+ mice. (F) Micrographs of curcumin+-Aβ plaques (yellow) or GFAP+ astrocytes (pink) in the cortices of BMWT versus BMACE10 AD+ chimeric mice. Scale bar = 50 μm. (G) Quantitative immunohistochemical (IHC) analysis of 6E10+-Aβ plaque area in the cortex of BMACE10 versus BMAD+ AD+-chimeric mice. (H) Quantitative IHC analysis of cortical GFAP+ astrocytosis area in AD+-chimeric mice. (I) Representative fluorescent micrographs of cortical brain regions stained against IGF-1 (red) combined with myeloid cell markers, IBA1 (white) and CD45 (green), and nuclei (DAPI, blue) in BMWT versus BMACE10 AD+-chimeric mice. Scale bars = 10 μm. Brain-infiltrating CD45hi IBA1+ ACE10-versus WT-Mo/MΦ highly expressed IGF-1 in AD+-chimeric mice. (J). Quantitative IHC analysis of % IGF-1+ area colocalized with Mo/MΦ in BMWT versus BMACE10 AD+-chimeric mice. (K) Quantitative flow cytometry analysis of TNFα expression levels in infiltrating ACE10-versus WT-MΦ (GFP+ CD11b+ CD45hi Ly6Cint-hi F4/80hi) in chimeric AD+ mice. (L) An additional study involved adoptive transfer of 5-6 million ACE10-or WT-CD115+ monocytes (MoBM) from young donor mice into the peripheral blood of 8-month-old AD+ mice. These inflammatory monocytes were isolated from the BM of GFP+ donor mice and enriched in the tube using the CD115-positive MACS column sorting procedure. ACE10- (MoACE10) or WT- (MoWT) BM were then injected into the tail vein of recipient AD+ mice. At the age of 11 months, mice underwent behavioral testing. (M) Barnes maze cognitive test: average errors count during the reversal phase, days 8 and 9. Statistics: (left) two-way ANOVA and Bonferroni’s post-test; (right) Day 9 memory test by one-way ANOVA and Bonferroni’s post test. (N) Severity of vascular Aβ deposits is defined as CAA score assessed with thioflavin-S (Thio-S+) staining in AD+ mice brain. (O) Quantitative IHC analysis of hippocampal pre-(VGluT1+) and post-(PSD95+) synaptic areas in MoACE10-treated mice compared to age- and gender-matched PBS-injected control AD+ and naïve WT mice. Illustration in panels A, B and L were created with Biorender.com, as well as images and graphs were used as original or modified from (Koronyo-Hamaoui et al., 2020) by permission of Oxford University Press.CC BY · PubMed Central
FIGURE 2 Enhanced clearance of Aβ42 assemblies by ACE-overexpressing macrophages. (A) In vitro experimental procedure: BM was isolated from young WT and ACE10 mice (8–12 weeks old) and cultured for 6 days with macrophage colony stimulating factor (MCSF)-enriched media, generating primary macrophage cultures (MΦWT and MΦACE10, respectively). On Day 7, MΦ were either unstimulated (Un) or stimulated by one of the 3 Aβ42 forms: fibrils (fAβ42), prion rod-like structures (pAβ42), or cross-linked oligomers (oAβ42). MΦACE10 were analyzed and compared to control MΦWT for cell surface Aβ42 binding and receptor expression as well as uptake of Aβ42 species at incremental time points from 5 to 15 min (incubated at 37°C). Additional experimental groups were pretreated at day 6 with the ACE inhibitor lisinopril, blocking its two catalytic domains. (B) Representative fluorescence micrograph of MΦWT and MΦACE10 cells that were incubated for 5 min with 250 nM fibril Aβ42 and later immunolabelled for Scara1 (red), human Aβ (6E10, green; white arrows indicate intracellular Aβ within vesicles in these phagocytic cells), and nuclei (DAPI, blue). (C) Quantitative immunocytochemistry (ICC) analysis of 6E10+ IR area (μm2/cell #) following intracellular uptake of the 3 Aβ42 species (fAβ42, pAβ42, or oAβ42) by MΦACE10 versus MΦWT in a period of 15 min. (D) Quantitative ICC of cell surface CD36 scavenger receptor expression (μm2/cell #) in MΦACE10 versus MΦWT following 15-min exposed to the three types of Aβ42 species. (E) Quantitative analysis of colocalized 6E10+ within EEA1+ endosomes in MΦWT versus MΦACE10 following exposure to the three types of Aβ42 species. (F) Representative flow cytometry peak analysis in % MFI of HiLyte Fluor 647-labelled fAβ42 uptake by MΦACE10 at the 0-, 5- and 15-min time points. (G) MFI analysis of HiLyte Fluor 647-labelled fAβ42 uptake by MΦACE10 at the 0-, 5- and 15-min time points, with and without lisinopril pretreatment. (H) MSD biochemical assay determined TNFα levels in MΦWT versus MΦACE10, either unstimulated (−) or stimulated (+) with Aβ42 fibrils [100 nM] for 24 h. MFI, Median Fluorescence Intensity. Illustration in panel A created with Biorender.com and other panels modified or adapted from (Koronyo-Hamaoui et al., 2020) by permission of Oxford University Press.
FIGURE 2 Enhanced clearance of Aβ42 assemblies by ACE-overexpressing macrophages. (A) In vitro experimental procedure: BM was isolated from young WT and ACE10 mice (8–12 weeks old) and cultured for 6 days with macrophage colony stimulating factor (MCSF)-enriched media, generating primary macrophage cultures (MΦWT and MΦACE10, respectively). On Day 7, MΦ were either unstimulated (Un) or stimulated by one of the 3 Aβ42 forms: fibrils (fAβ42), prion rod-like structures (pAβ42), or cross-linked oligomers (oAβ42). MΦACE10 were analyzed and compared to control MΦWT for cell surface Aβ42 binding and receptor expression as well as uptake of Aβ42 species at incremental time points from 5 to 15 min (incubated at 37°C). Additional experimental groups were pretreated at day 6 with the ACE inhibitor lisinopril, blocking its two catalytic domains. (B) Representative fluorescence micrograph of MΦWT and MΦACE10 cells that were incubated for 5 min with 250 nM fibril Aβ42 and later immunolabelled for Scara1 (red), human Aβ (6E10, green; white arrows indicate intracellular Aβ within vesicles in these phagocytic cells), and nuclei (DAPI, blue). (C) Quantitative immunocytochemistry (ICC) analysis of 6E10+ IR area (μm2/cell #) following intracellular uptake of the 3 Aβ42 species (fAβ42, pAβ42, or oAβ42) by MΦACE10 versus MΦWT in a period of 15 min. (D) Quantitative ICC of cell surface CD36 scavenger receptor expression (μm2/cell #) in MΦACE10 versus MΦWT following 15-min exposed to the three types of Aβ42 species. (E) Quantitative analysis of colocalized 6E10+ within EEA1+ endosomes in MΦWT versus MΦACE10 following exposure to the three types of Aβ42 species. (F) Representative flow cytometry peak analysis in % MFI of HiLyte Fluor 647-labelled fAβ42 uptake by MΦACE10 at the 0-, 5- and 15-min time points. (G) MFI analysis of HiLyte Fluor 647-labelled fAβ42 uptake by MΦACE10 at the 0-, 5- and 15-min time points, with and without lisinopril pretreatment. (H) MSD biochemical assay determined TNFα levels in MΦWT versus MΦACE10, either unstimulated (−) or stimulated (+) with Aβ42 fibrils [100 nM] for 24 h. MFI, Median Fluorescence Intensity. Illustration in panel A created with Biorender.com and other panels modified or adapted from (Koronyo-Hamaoui et al., 2020) by permission of Oxford University Press.CC BY · PubMed Central
FIGURE 3 Proposed mechanism for neuroprotective role of ACE overexpression in monocytes in AD. (A) ACE overexpression under the activation of the c-fms promotor in CD115+ monocytes is named ACE10 model. CD115+ ACE10-monocytes exhibit a neuroprotective phenotype with lower expression of pro-inflammatory mediators such as iNOS and TNFα and increased expression of the neurotrophic factor IGF-1, Aβ-degrading enzymes (ACE, MMP-9), and surface scavenger receptors as CD36 and Scara-1 that facilitate phagocytosis of Aβ. (B) CD115+ ACE10-monocytes are recruited in larger numbers than WT monocytes to AD-like brains and retinas, resulting in neuro-immunomodulation. The ACE10 monocyte-derived macrophages aggregate at areas of amyloid plaque deposition and facilitate the clearance of Aβ oligomers and plaques. This is concomitant with reduced microgliosis and astrogliosis. Notably, in the ACE10 versus WT macrophages, there is increased presence of Aβ assemblies within EEA1 endosomes, suggesting enhanced intracellular lysosomal Aβ degradation machinery in ACE10 macrophages. (C) Murine models of AD treated with ACE10 monocytes show reduced AD-related pathology, preservation of excitatory synapses, and (D) improved cognitive functions. Created with Biorender.com.
FIGURE 3 Proposed mechanism for neuroprotective role of ACE overexpression in monocytes in AD. (A) ACE overexpression under the activation of the c-fms promotor in CD115+ monocytes is named ACE10 model. CD115+ ACE10-monocytes exhibit a neuroprotective phenotype with lower expression of pro-inflammatory mediators such as iNOS and TNFα and increased expression of the neurotrophic factor IGF-1, Aβ-degrading enzymes (ACE, MMP-9), and surface scavenger receptors as CD36 and Scara-1 that facilitate phagocytosis of Aβ. (B) CD115+ ACE10-monocytes are recruited in larger numbers than WT monocytes to AD-like brains and retinas, resulting in neuro-immunomodulation. The ACE10 monocyte-derived macrophages aggregate at areas of amyloid plaque deposition and facilitate the clearance of Aβ oligomers and plaques. This is concomitant with reduced microgliosis and astrogliosis. Notably, in the ACE10 versus WT macrophages, there is increased presence of Aβ assemblies within EEA1 endosomes, suggesting enhanced intracellular lysosomal Aβ degradation machinery in ACE10 macrophages. (C) Murine models of AD treated with ACE10 monocytes show reduced AD-related pathology, preservation of excitatory synapses, and (D) improved cognitive functions. Created with Biorender.com.CC BY · PubMed Central

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Metadata

Authors
Danziger, R., Fuchs, D.-T., Koronyo, Y., Rentsendorj, A., Sheyn, J., Hayden, E. Y., Teplow, D. B., Black, K. L., Fuchs, S., Bernstein, K. E., & Koronyo-Hamaoui, M.
Venue
Frontiers in Physiology
Publisher
Frontiers Media SA
Published
2023-06-23
Volume
14
ISSN
1664-042X
DOI
10.3389/fphys.2023.1179315
PMC
PMC10326285
Cited by
16
References
15
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • National Institute on Aging (R01 AG042195 R01 AG056478 R01 AG075998 R01 AG055865)
  • BrightFocus Foundation (A2013328S00)
  • Coins for Alzheimer’s Research Trust (CART fund)
  • Clinical and Translational Science Institute, University of California, Los Angeles (UL1TR000124)

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