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Angiotensin Converting Enzyme Inhibitors Ameliorate Brain Inflammation Associated with Microglial Activation: Possible Implications for Alzheimer’s Disease

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Abstract

Angiotensin converting enzyme (ACE) converts Angiotensin I to a potent vasoconstrictor angiotensin II (ANG II). ACE inhibitors (ACEIs) are widely used for the management of hypertension. All components of the renin-angiotensin system (RAS) have also been identified in the brain. In addition to cytokines, neuromodulators such as ANG II can induce neuroinflammation. Moreover, in Alzheimer’s disease (AD) models, where neuroinflammation occurs and is thought to contribute to the propagation of the disease, increased levels of ANG II and ACE have been detected. However, the specific effect of ACEIs on neuroinflammation and AD remains obscure. The present study suggests that captopril and perindopril, centrally active ACEIs, may serve as modulators for microglial activation associated with AD. Our in vitro study investigated the effect of both ACEIs on nitric oxide (NO), tumor necrosis factor- α (TNF-α) release and inducible NO synthase (iNOS) expression in lipopolysaccharide (LPS)-induced BV2 microglia. Exposure of BV2 microglia to ACEIs significantly attenuated the LPS-induced NO and TNF-α release. In vivo, short term intranasal administration of perindopril or captopril to 5 Familial AD (5XFAD) mice significantly reduced amyloid burden and CD11b expression (a microglial marker) or only CD11b expression respectively, in the cortex of 5XFAD. Long-term intranasal administration of captopril to mice reduced amyloid burden with no effect on CD11b expression. We provide evidence that intranasal delivery of ACEI may serve as an efficient alternative for their systemic administration, as it results in the attenuation of microglial accumulation and even the reduction of Amyloid β (Aβ) plaques.

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Acknowledgments

We thank Prof. Rosario Donato (Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Italy) for providing us the BV2 murine microglial cell line.

Five familial alzheimer’s disease mice were kindly provided by Prof. Robert Vassar (Department of Cell and Molecular Biology, Northwestern University, Chicago, Illinois).

Rabbit anti human Aβ antibody was received as a gift from Prof. Alon Monsonego, (The Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences and the National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel).

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    1. Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, P.O, B 653, Beer-Sheva, Israel

      Nofar Torika, Keren Asraf, Ella Roasso, Abraham Danon & Sigal Fleisher-Berkovich

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    1. Nofar Torika
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    Correspondence to Sigal Fleisher-Berkovich.

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    This study was funded by the Israel Science Foundation (ISF) grant to Sigal Fleisher-Berkovich no: 101/11–16.

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    Nofar Torika and Keren Asraf equally contributed to this paper

    This research was supported by the Israel Science Foundation (grant No 101/11–16)

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    Torika, N., Asraf, K., Roasso, E. et al. Angiotensin Converting Enzyme Inhibitors Ameliorate Brain Inflammation Associated with Microglial Activation: Possible Implications for Alzheimer’s Disease. J Neuroimmune Pharmacol 11, 774–785 (2016). https://doi.org/10.1007/s11481-016-9703-8

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