Pro-inflammatory conditions promote neuronal damage mediated by Amyloid Precursor Protein and decrease its phagocytosis and degradation by microglial cells in culture.
Aberrant handling of Amyloid Precursor Protein (APP) and beta-amyloid (Abeta), glial activation and inflammation are key events in Alzheimer's disease. We set out to determine the role of inflammation on microglial reactivity against APP. We studied microglia-mediated neurotoxicity, uptake and degradation of a biotinylated APP construct (biotin-APP-C-244). APP, in contrast to Abeta, only induced mild activation of glial cells. However, under pro-inflammatory conditions, APP induced microglial-mediated cytotoxicity. Biotin-APP-C-244 or lipopolysaccharide and interferon-gamma (LPS+IFNgamma), administered separately, did not change reduction metabolism of microglia. However, biotin-APP-C-244+(LPS+IFNgamma) increased microglial reactivity and decreased reduction metabolism by 75% (P<0.001). Biotin-APP-C-244 was readily taken up by microglial cells; 80% was phagocytosed at 2 h. In the presence of LPS+IFNgamma, phagocytosis of biotin-APP-C-244 was reduced at 2 h; and cell damage was evident after 4 h. Our results support our hypothesis that, in neuroinflammation, microglial scavenger function is impaired and reactivity against APP enhanced as an initial step for neurodegeneration.
von Bernhardi
Rommy
R
Department of Neurology, Faculty of Medicine, Pontificia Universidad Católica de Chile Marcoleta 391, Santiago, Chile. rvonb@med.puc.cl
Ramírez
Gigliola
G
Toro
Rodrigo
R
Eugenín
Jaime
J
D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects; D001710:Biotin / Q000737:chemistry; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D006735:Horseradish Peroxidase; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology*; D017628:Microglia / Q000502:physiology*; D009474:Neurons / Q000473:pathology*; D010587:Phagocytosis / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012710:Serum Albumin, Bovine / Q000737:chemistry; D019809:Streptavidin; D013778:Tetrazolium Salts; D013844:Thiazoles
D016564:Amyloid beta-Protein Precursor; D013778:Tetrazolium Salts; D013844:Thiazoles; D012710:Serum Albumin, Bovine; D001710:Biotin; D019809:Streptavidin; D006735:Horseradish Peroxidase; C022616:thiazolyl blue