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

Ron Danziger; Dieu-Trang Fuchs; Yosef Koronyo; Altan Rentsendorj; Julia Sheyn; Eric Y Hayden; David B Teplow; Keith L Black; Sebastien Fuchs; Kenneth E Bernstein; Maya Koronyo-Hamaoui

doi:10.3389/fphys.2023.1179315

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

Front Physiol. 2023 Jun 23:14:1179315. doi: 10.3389/fphys.2023.1179315. eCollection 2023.

Authors

Ron Danziger^{1

2}, Dieu-Trang Fuchs¹, Yosef Koronyo¹, Altan Rentsendorj¹, Julia Sheyn¹, Eric Y Hayden³, David B Teplow³, Keith L Black¹, Sebastien Fuchs⁴, Kenneth E Bernstein^{5

6}, Maya Koronyo-Hamaoui^{1

2

5}

Affiliations

¹ Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical center, Los Angeles, CA, United States.
² Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
³ Department of Neurology, David Geffen School of Medicine at UCLA, Mary S. Easton Center for Alzheimer's Disease Research at UCLA, Brain Research Institute, Molecular Biology Institute, University of California, Los Angeles, CA, United States.
⁴ College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States.
⁵ Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
⁶ Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States.

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 (Aβ₄₂), 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 Aβ₄₂ 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.

Keywords: degrading peptidase; innate immune cells; macrophages; microglia; monocytes; neurodegenerative diseases; neuroscience; pro-inflammatory cytokines.

Publication types

Review

Abstract

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