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Front Mol Neurosci. 2017 Jun 30;10:206. doi: 10.3389/fnmol.2017.00206. eCollection 2017.

Increased White Matter Inflammation in Aging- and Alzheimer's Disease Brain.

Author information

1
Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen, University of GroningenGroningen, Netherlands.
2
Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, China.
3
Department of Pathology, VU University Medical CenterAmsterdam, Netherlands.
4
Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of GroningenGroningen, Netherlands.
5
Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of AntwerpWilrijk, Belgium.
6
Department of Neurology and Alzheimer Research Center, University Medical Center Groningen, University of GroningenGroningen, Netherlands.
7
Biobank, Institute Born-BungeWilrijk, Belgium.
8
Department of Pathology, University Medical Center Groningen, University of GroningenGroningen, Netherlands.
9
Neuroimmunology Unit, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and DentistryLondon, United Kingdom.

Abstract

Chronic neuroinflammation, which is primarily mediated by microglia, plays an essential role in aging and neurodegeneration. It is still unclear whether this microglia-induced neuroinflammation occurs globally or is confined to distinct brain regions. In this study, we investigated microglia activity in various brain regions upon healthy aging and Alzheimer's disease (AD)-related pathology in both human and mouse samples. In purified microglia isolated from aging mouse brains, we found a profound gene expression pattern related to pro-inflammatory processes, phagocytosis, and lipid homeostasis. Particularly in white matter microglia of 24-month-old mice, abundant expression of phagocytic markers including Mac-2, Axl, CD16/32, Dectin1, CD11c, and CD36 was detected. Interestingly, in white matter of human brain tissue the first signs of inflammatory activity were already detected during middle age. Thus quantification of microglial proteins, such as CD68 (commonly associated with phagocytosis) and HLA-DR (associated with antigen presentation), in postmortem human white matter brain tissue showed an age-dependent increase in immunoreactivity already in middle-aged people (53.2 ± 2.0 years). This early inflammation was also detectable by non-invasive positron emission tomography imaging using [11C]-(R)-PK11195, a ligand that binds to activated microglia. Increased microglia activity was also prominently present in the white matter of human postmortem early-onset AD (EOAD) brain tissue. Interestingly, microglia activity in the white matter of late-onset AD (LOAD) CNS was similar to that of the aged clinically silent AD cases. These data indicate that microglia-induced neuroinflammation is predominant in the white matter of aging mice and humans as well as in EOAD brains. This white matter inflammation may contribute to the progression of neurodegeneration, and have prognostic value for detecting the onset and progression of aging and neurodegeneration.

KEYWORDS:

Alzheimer’s disease; aging; microglia; neuroinflammation; white matter

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