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      Brain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer Aβ Peptides

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          Abstract

          Rationale

          Increasing evidence indicates that alterations of the cerebral microcirculation may play a role in Alzheimer’s disease (AD), the leading cause of late-life dementia. The amyloid-β peptide (Aβ), a key pathogenic factor in AD, induces profound alterations in neurovascular regulation through the innate immunity receptor CD36, which, in turn, activates a Nox2-containing NADPH oxidase leading to cerebrovascular oxidative stress. Brain perivascular macrophages (PVM) located in the perivascular space, a major site of brain Aβ collection and clearance, are juxtaposed to the wall of intracerebral resistance vessels and are a powerful source of reactive oxygen species (ROS).

          Objective

          We tested the hypothesis that PVM are the main source of ROS responsible for the cerebrovascular actions of Aβ, and that CD36 and Nox2 in PVM are the molecular substrates of the effect.

          Methods and Results

          Selective depletion of PVM using intracerebroventricular injection of clodronate abrogates the ROS production and cerebrovascular dysfunction induced by Aβ applied directly to the cerebral cortex, administered intravascularly or overproduced in the brain of transgenic mice expressing mutated forms of the amyloid precursor protein (Tg2576 mice). In addition, using bone marrow chimeras we demonstrate that PVM are the cells expressing CD36 and Nox2 responsible for the dysfunction. Thus, deletion of CD36 or Nox2 from PVM abrogates the deleterious vascular effects of Aβ, whereas wild-type PVM reconstitute the vascular dysfunction in CD36-null mice.

          Conclusions

          The data identify PVM as a previously unrecognized effector of the damaging neurovascular actions of Aβ and unveil a new mechanism by which brain-resident innate immune cells and their receptors may contribute to the pathobiology of AD.

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          Author and article information

          Journal
          0047103
          2974
          Circ Res
          Circ. Res.
          Circulation research
          0009-7330
          1524-4571
          25 May 2017
          17 May 2017
          21 July 2017
          21 July 2018
          : 121
          : 3
          : 258-269
          Affiliations
          [1 ]Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY
          [2 ]McLaughlin Research Institute, Great Falls, MT
          [3 ]Mayo Clinic Jacksonville, Jacksonville, FL
          Author notes
          Address correspondence to: Dr. Laibaik Park, Feil Family Brain and Mind Research Institute, 407 East 61 st Street, Room RR410, New York, NY 10065, Tel: 646-962-8255, lap2003@ 123456med.cornell.edu . Dr. Costantino Iadecola, Feil Family Brain and Mind Research Institute,407 East 61 st Street, Room 303, New York, NY 10065, Phone: 646-962-8279, coi2001@ 123456med.cornell.edu
          Article
          PMC5522360 PMC5522360 5522360 nihpa877716
          10.1161/CIRCRESAHA.117.311054
          5522360
          28515043
          f1688eb1-e76e-4895-80b8-52ddc2177c8e
          Categories
          Article

          cerebrovascular disease,oxidative stress,endothelium,perivascular macrophages,Animal Models of Human Disease,Basic Science Research,Vascular Biology,Endothelium/Vascular Type/Nitric Oxide,Oxidant Stress,Vascular biology

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