Brain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer A? Peptides.

ABSTRACT: RATIONALE:Increasing evidence indicates that alterations of the cerebral microcirculation may play a role in Alzheimer disease, the leading cause of late-life dementia. The amyloid-? peptide (A?), a key pathogenic factor in Alzheimer disease, induces profound alterations in neurovascular regulation through the innate immunity receptor CD36 (cluster of differentiation 36), 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 A? collection and clearance, are juxtaposed to the wall of intracerebral resistance vessels and are a powerful source of reactive oxygen species. OBJECTIVE:We tested the hypothesis that PVM are the main source of reactive oxygen species responsible for the cerebrovascular actions of A? 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 reactive oxygen species production and cerebrovascular dysfunction induced by A? 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 A?, 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 A? and unveil a new mechanism by which brain-resident innate immune cells and their receptors may contribute to the pathobiology of Alzheimer disease.

SUBMITTER: Park L 

PROVIDER: S-EPMC5522360 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature