Transport of cargo from periphery to brain by circulating monocytes

• Type of Material: Article
• Authors: Amarallys F. Cintron, Emory University; Nirjari V. Dalal, Emory University; Jeromy Dooyema, Emory University; Ranjita Betarbet, Emory University; Lary Walker, Emory University
• Language: English
• Date: 2015-10-05
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 Elsevier B.V.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.brainres.2015.06.047
• Title of Journal or Parent Work: Brain Research
• ISSN: 0006-8993
• Volume: 1622
• Start Page: 328
• End Page: 338
• Grant/Funding Information: This work was supported by R36AG043646, R21AG040589, RR00165, T32 NS007480-14, and by the MetLife Foundation.
• Keywords: Prion; NEURODEGENERATIVE DISEASES; PATHOGENIC PROTEINS; Neurosciences; Macrophage; Neurosciences & Neurology; Alzheimer's disease; INTRAOCULAR INOCULATION; Science & Technology; Cerebral amyloid angiopathy; TO-NEURON TRANSMISSION; Amyloid; A beta; TRANSGENIC MICE; GASTROINTESTINAL-TRACT; CENTRAL-NERVOUS-SYSTEM; Life Sciences & Biomedicine
• Research Categories: Biology, Neuroscience; Health Sciences, Pathology

Abstract

The misfolding and aggregation of the Aβ peptide - a fundamental event in the pathogenesis of Alzheimer's disease - can be instigated in the brains of experimental animals by the intracranial infusion of brain extracts that are rich in aggregated Aβ. Recent experiments have found that the peripheral (intraperitoneal) injection of Aβ seeds induces Aβ deposition in the brains of APP-transgenic mice, largely in the form of cerebral amyloid angiopathy. Macrophage-type cells normally are involved in pathogen neutralization and antigen presentation, but under some circumstances, circulating monocytes have been found to act as vectors for the transport of pathogenic agents such as viruses and prions. The present study assessed the ability of peripheral monocytes to transport Aβ aggregates from the peritoneal cavity to the brain. Our initial experiments showed that intravenously delivered macrophages that had previously ingested fluorescent nanobeads as tracers migrate primarily to peripheral organs such as spleen and liver, but that a small number also reach the brain parenchyma. We next injected CD45.1-expressing monocytes from donor mice intravenously into CD45.2-expressing host mice; after 24 h, analysis by fluorescence-activated cell sorting (FACS) and histology confirmed that some CD45.1 monocytes enter the brain, particularly in the superficial cortex and around blood vessels. When the donor monocytes are first exposed to Aβ-rich brain extracts from human AD cases, a subset of intravenously delivered Aβ-containing cells migrate to the brain. These experiments indicate that, in mouse models, circulating monocytes are potential vectors by which exogenously delivered, aggregated Aβ travels from periphery to brain, and more generally support the hypothesis that macrophage-type cells can participate in the dissemination of proteopathic seeds.