Brain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer Aβ Peptides

Laibaik Park, Ken Uekawa, Lidia Garcia-Bonilla, Kenzo Koizumi, Michelle Murphy, Rose Pistik, Linda Younkin, Steven G Younkin, Ping Zhou, George Carlson, Josef Anrather, Costantino Iadecola

Research output: Contribution to journalArticle

41 Citations (Scopus)

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-β peptide (Aβ), 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 Aβ 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 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 reactive oxygen species 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 Alzheimer disease.

Original languageEnglish (US)
Pages (from-to)258-269
Number of pages12
JournalCirculation Research
Volume121
Issue number3
DOIs
StatePublished - Jul 21 2017

Fingerprint

Macrophages
Peptides
Brain
Reactive Oxygen Species
Alzheimer Disease
Blood Vessels
Clodronic Acid
Amyloid beta-Protein Precursor
NADPH Oxidase
Microcirculation
Amyloid
Innate Immunity
Cerebral Cortex
Transgenic Mice
Dementia
Oxidative Stress
Bone Marrow
Injections

Keywords

  • Alzheimer disease
  • brain
  • cerebrovascular disease
  • endothelium
  • oxidative stress

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Park, L., Uekawa, K., Garcia-Bonilla, L., Koizumi, K., Murphy, M., Pistik, R., ... Iadecola, C. (2017). Brain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer Aβ Peptides. Circulation Research, 121(3), 258-269. https://doi.org/10.1161/CIRCRESAHA.117.311054

Brain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer Aβ Peptides. / Park, Laibaik; Uekawa, Ken; Garcia-Bonilla, Lidia; Koizumi, Kenzo; Murphy, Michelle; Pistik, Rose; Younkin, Linda; Younkin, Steven G; Zhou, Ping; Carlson, George; Anrather, Josef; Iadecola, Costantino.

In: Circulation Research, Vol. 121, No. 3, 21.07.2017, p. 258-269.

Research output: Contribution to journalArticle

Park, L, Uekawa, K, Garcia-Bonilla, L, Koizumi, K, Murphy, M, Pistik, R, Younkin, L, Younkin, SG, Zhou, P, Carlson, G, Anrather, J & Iadecola, C 2017, 'Brain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer Aβ Peptides', Circulation Research, vol. 121, no. 3, pp. 258-269. https://doi.org/10.1161/CIRCRESAHA.117.311054
Park, Laibaik ; Uekawa, Ken ; Garcia-Bonilla, Lidia ; Koizumi, Kenzo ; Murphy, Michelle ; Pistik, Rose ; Younkin, Linda ; Younkin, Steven G ; Zhou, Ping ; Carlson, George ; Anrather, Josef ; Iadecola, Costantino. / Brain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer Aβ Peptides. In: Circulation Research. 2017 ; Vol. 121, No. 3. pp. 258-269.
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