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


  • Department of Medicine, West Los Angeles VA Medical Center (Q. N. Liu, V. Pop, V. Brahmandam); Departments of Neurology (M. C. Graves, H. V. Vinters), Pathology and Laboratory Medicine (Neuropathology) (H. V. Vinters), Brain Research Institute, Los Angeles, CA (M. Fiala, H. V. Vinters); Neuropsychiatric Institute, UCLA School of Medicine, Los Angeles, CA (H. V. Vinters); UCLA School of Public Health (J. Sayre), Los Angeles, CA.

Milan Fiala, Cardiovascular Research Laboratory, UCLA, 3645 MRL, 675 Young Drive South, Los Angeles, CA 90095–1760, USA. Tel.: +310 206 6392; fax: +310 825 1678; e-mail:


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.