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Citations to this article

Angiotensin-converting enzyme overexpression in myelomonocytes prevents Alzheimer’s-like cognitive decline
Kenneth E. Bernstein, … , Sebastien Fuchs, Maya Koronyo-Hamaoui
Kenneth E. Bernstein, … , Sebastien Fuchs, Maya Koronyo-Hamaoui
Published February 3, 2014
Citation Information: J Clin Invest. 2014;124(3):1000-1012. https://doi.org/10.1172/JCI66541.
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Research Article Neuroscience

Angiotensin-converting enzyme overexpression in myelomonocytes prevents Alzheimer’s-like cognitive decline

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Abstract

Cognitive decline in patients with Alzheimer’s disease (AD) is associated with elevated brain levels of amyloid β protein (Aβ), particularly neurotoxic Aβ1–42. Angiotensin-converting enzyme (ACE) can degrade Aβ1–42, and ACE overexpression in myelomonocytic cells enhances their immune function. To examine the effect of targeted ACE overexpression on AD, we crossed ACE10/10 mice, which overexpress ACE in myelomonocytes using the c-fms promoter, with the transgenic APPSWE/PS1ΔE9 mouse model of AD (AD+). Evaluation of brain tissue from these AD+ACE10/10 mice at 7 and 13 months revealed that levels of both soluble and insoluble brain Aβ1–42 were reduced compared with those in AD+ mice. Furthermore, both plaque burden and astrogliosis were drastically reduced. Administration of the ACE inhibitor ramipril increased Aβ levels in AD+ACE10/10 mice compared with the levels induced by the ACE-independent vasodilator hydralazine. Overall, AD+ACE10/10 mice had less brain-infiltrating cells, consistent with reduced AD-associated pathology, though ACE-overexpressing macrophages were abundant around and engulfing Aβ plaques. At 11 and 12 months of age, the AD+ACE10/WT and AD+ACE10/10 mice were virtually equivalent to non-AD mice in cognitive ability, as assessed by maze-based behavioral tests. Our data demonstrate that an enhanced immune response, coupled with increased myelomonocytic expression of catalytically active ACE, prevents cognitive decline in a murine model of AD.

Authors

Kenneth E. Bernstein, Yosef Koronyo, Brenda C. Salumbides, Julia Sheyn, Lindsey Pelissier, Dahabada H.J. Lopes, Kandarp H. Shah, Ellen A. Bernstein, Dieu-Trang Fuchs, Jeff J.-Y. Yu, Michael Pham, Keith L. Black, Xiao Z. Shen, Sebastien Fuchs, Maya Koronyo-Hamaoui

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