Cyclooxygenase‐2‐positive macrophages infiltrate the Alzheimer’s disease brain and damage the blood–brain barrier
Abstract
Background Monocyte/macrophages are known to infiltrate the brain of patients with HIV‐1 encephalitis (HIVE). In Alzheimer’s disease brain, the origin of activated microglia has not been determined. Materials and methods We employed the antigen retrieval technique, immunocytochemistry, immunofluorescense, and confocal microscopy to identify macrophages and microglia in relation to amyloid‐β plaques and the blood–brain barrier in autopsy brain tissues from patients with Alzheimer’s disease (AD) and HIVE. Results In both conditions, cyclooxygenase‐2 positive macrophages and, to a lesser degree, T and B cells infiltrate brain perivascular spaces and neuropil. The macrophages are distinguishable from ramified microglia, and decorate the vessels at the sites of apparent of endothelial tight junction protein ZO‐1 disruption. The macrophages also infiltrate amyloid‐β plaques, display intracellular amyloid‐β and are surrounded by amyloid‐β‐free lacunae. Furthermore, the macrophages partially encircle the walls of amyloid‐β‐containing vessels in amyloid angiopathy, and exhibit intracellular amyloid‐β but not paracellular lacunae. Significantly larger zones of fibrinogen leakage surround the microvessels in HIVE brain tissues compared with AD tissues (P = 0·034), and AD tissues have significantly greater leakage than control tissues (P = 0·0339). The AD group differs from a normal control age‐matched group with respect to both the area occupied by CD68 (P = 0·03) and cyclooxygenase‐2 immunoreactive cells (P = 0·004). Conclusion In both HIVE and AD, blood‐borne activated monocyte/macrophages and lymphocytes appear to migrate through a disrupted blood–brain barrier. The lacunae around macrophages in amyloid‐β plaques but not in vessel walls are consistent with the ability of macrophages to phagocytize and clear amyloid‐β deposits in vitro.
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RBC extravasation and brain infiltration by peripheral macrophages and neutrophils are reported in Alzheimer's disease post mortem studies.
“RBC extravasation (125) and brain infiltration by peripheral macrophages (175, 267) and neutrophils (676) are reported in AD post mortem studies”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [175]
CD68 is primarily localized to microglia within the brain parenchyma, and to perivascular macrophages in the cerebral blood vessels and occasionally parenchyma.
“CD68 is a common marker for macrophage lineage cells, primarily localized to microglia within the brain parenchyma, and perivascular macrophages in the cerebral blood vessels and, occasionally, parenchyma.78”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [78]
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- Authors
- Fiala, M., Liu, Q. N., Sayre, J., Pop, V., Brahmandam, V., Graves, M. C., & Vinters, H. V.
- Affiliations
- University of California, Los Angeles (US)
- VA West Los Angeles Medical Center (US)
- Corresponding author
- Fiala, M.
- Venue
- European Journal of Clinical Investigation
- Publisher
- Wiley
- Published
- 2002-05
- Volume
- 32
- Issue
- 5
- Pages
- 360-371
- ISSN
- 0014-2972 (ISSN-L)
- 1365-2362
- OpenAlex
- W2156944982
- Cited by
- 307
- References
- 8
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 18 · 2023: 18 · 2022: 20 · 2021: 15 · 2020: 11 · 2019: 13 · 2018: 19 · 2017: 15 · 2016: 11 · 2015: 16 · 2014: 17 · 2013: 8 · 2012: 13
- FWCI
- 5.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Clinical Investigation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01da010442-02)
- National Institute on Aging (P01AG 12435, P50AG016570, P50-AG 16570, P01AG012435)
- National Institute of Mental Health (R24MH059656, R24-MH-59724, R24MH059724, R24 MH59656)
- National Institute on Drug Abuse (DA 10442)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- cyclooxygenase-2, macrophages, Alzheimer's disease, HIV-1 encephalitis, blood-brain barrier disruption, amyloid plaques, amyloid angiopathy, microglia, ZO-1 tight junction, CD68, monocyte/macrophage infiltration
- MeSH terms
- CD68 Molecule, Adult, Aged, Aged, 80 and over, Alzheimer Disease, Blood-Brain Barrier, Brain, Cerebrovascular Circulation, Humans, Immunohistochemistry, Isoenzymes, Lymphocytes, Macrophages, Male, Membrane Proteins, Middle Aged, Peptide Fragments, Prostaglandin-Endoperoxide Synthases, Antigens, Differentiation, Myelomonocytic, HIV-1, AIDS Dementia Complex, Antigens, CD, Amyloid beta-Peptides, Tight Junctions, Cyclooxygenase 2
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