Brain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer Aβ Peptides

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.

Brain perivascular macrophages: characterization and functional roles in health and disease

“…Aβ impairs the increase in cerebral blood flow produced by neural activity and induces endothelial dysfunction, effects dependent on vascular oxidative stress produced by a Nox2-containing NADPH oxidase [42]. Selective depletion of PVM abrogated the vascular oxidative stress and neurovascular alterations induced by Aβ either applied directly to the neocortex of wild-type mice or produced endogenously in Tg2576 mice overexpressing mutated APP [43]. PVM were also needed for the neurovascular dysfunction induced by circulating Aβ, an effect mediated by Aβ entering the perivascular space and reaching PVM to induce vascular oxidative stress [43].…”

“…Selective depletion of PVM abrogated the vascular oxidative stress and neurovascular alterations induced by Aβ either applied directly to the neocortex of wild-type mice or produced endogenously in Tg2576 mice overexpressing mutated APP [43]. PVM were also needed for the neurovascular dysfunction induced by circulating Aβ, an effect mediated by Aβ entering the perivascular space and reaching PVM to induce vascular oxidative stress [43]. The cerebrovascular dysfunction was abolished in Tg2576 mice transplanted with CD36- or Nox2-deficient BM [43].…”

“…PVM were also needed for the neurovascular dysfunction induced by circulating Aβ, an effect mediated by Aβ entering the perivascular space and reaching PVM to induce vascular oxidative stress [43]. The cerebrovascular dysfunction was abolished in Tg2576 mice transplanted with CD36- or Nox2-deficient BM [43]. Furthermore, transplant of CD36+ BM reinstated the neurovascular dysfunction induced by Aβ in CD36-deficient mice [43], suggesting that the CD36-Nox2 signaling pathway in PVM is required for the deleterious cerebrovascular effects of Aβ.…”

“…The cerebrovascular dysfunction was abolished in Tg2576 mice transplanted with CD36- or Nox2-deficient BM [43]. Furthermore, transplant of CD36+ BM reinstated the neurovascular dysfunction induced by Aβ in CD36-deficient mice [43], suggesting that the CD36-Nox2 signaling pathway in PVM is required for the deleterious cerebrovascular effects of Aβ. These findings, collectively, could implicate PVM in AD pathophysiology and suggest that PVM scavenger receptors, including SR-BI or CD36, are crucial in modulating the accumulation of Aβ in the brain and related neurovascular effects.…”

Disease Highlights the Cellular Diversity of Neurovascular Units

“…8 To pursue this question, complementary approaches were used that included alterations in local levels of Aβ, pharmacological and genetic manipulation of PVM numbers and genotype, focusing on the role of Nox2 and CD36, a receptor that activates NADPH oxidase in the PVM. The study relied on two models, one that examined acute effects of Aβ 1–40 , and the second, a genetic model that chronically expresses a Swedish mutation in amyloid precursor protein (APP).…”