Cyclooxygenase-2-positive macrophages infiltrate the Alzheimer's disease brain and damage the blood-brain barrier

Eur J Clin Invest. 2002 May;32(5):360-71. doi: 10.1046/j.1365-2362.2002.00994.x.


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-beta 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-beta plaques, display intracellular amyloid-beta and are surrounded by amyloid-beta-free lacunae. Furthermore, the macrophages partially encircle the walls of amyloid-beta-containing vessels in amyloid angiopathy, and exhibit intracellular amyloid-beta 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-beta plaques but not in vessel walls are consistent with the ability of macrophages to phagocytize and clear amyloid-beta deposits in vitro.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • AIDS Dementia Complex / immunology*
  • AIDS Dementia Complex / metabolism
  • AIDS Dementia Complex / pathology
  • Adult
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / immunology*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism
  • Antigens, CD / immunology
  • Antigens, CD / metabolism*
  • Antigens, Differentiation, Myelomonocytic / immunology
  • Antigens, Differentiation, Myelomonocytic / metabolism*
  • Blood-Brain Barrier*
  • Brain / metabolism*
  • Brain / pathology
  • Cerebrovascular Circulation
  • Cyclooxygenase 2
  • HIV-1
  • Humans
  • Immunohistochemistry
  • Isoenzymes / metabolism*
  • Lymphocytes / physiology
  • Macrophages / physiology*
  • Male
  • Membrane Proteins
  • Middle Aged
  • Peptide Fragments / metabolism
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Tight Junctions / metabolism


  • Amyloid beta-Peptides
  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • CD68 antigen, human
  • Isoenzymes
  • Membrane Proteins
  • Peptide Fragments
  • amyloid beta-protein (1-34)
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases