Activation of NR1a/NR2B receptors by soluble factors from APP-stimulated monocyte-derived macrophages: implications for the pathogenesis of Alzheimer's disease.
Amyloid-beta peptide (Abeta), the major component of amyloid plaques, can activate brain mononuclear phagocytes (MP; macrophages and microglia), leading to their secretion of neurotoxins. Recent studies strongly suggest that MP-mediated neurotoxicity plays an important role in the pathogenesis of Alzheimer's disease (AD). To further explore this notion, human monocyte-derived macrophages (MDM) were stimulated with naturally secreted alpha-processing soluble amyloid precursor protein/p3 (alphaAPPs/p3) or beta-processing APP/Abeta (betaAPPs/Abeta). MDM conditioned media (MCM) was recovered and tested for its ability to activate recombinant N-methyl-d-aspartate (NMDA) receptor subtype NR1a/NR2B expressed in Xenopus oocytes. Pressure ejection of alphaAPPs/p3- and betaAPPs/Abeta-stimulated MCM produced inward currents of 59.5 +/- 8.9 nA (mean +/- S.E.M., n = 31) and 111.1 +/- 21.0 nA (n = 42) in NR1a/NR2B-expressing oocytes, respectively. The MCM-induced currents were concentration dependent and blocked by 50 microM of the NMDA receptor antagonist 2-amino-5-phosphnovalerate, but not by a non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (20 microM). The alphaAPPs/p3- and betaAPPs/Abeta-stimulated MCM placed in non-injected oocytes failed to generate inward current. These results demonstrate that APPs/Abeta-stimulated MCM directly activate NMDA receptor subtypes relevant in the pathogenesis of AD.
Xiong
Huangui
H
The Laboratory of Neurophysiology, University of Nebraska Medical Center, Omaha, NE 68198-5215, USA. hxiong@unmc.edu
McCabe
Laura
L
Costello
Joseph
J
Anderson
Eric
E
Weber
Gregory
G
Ikezu
Tsuneya
T
D000544:Alzheimer Disease / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001685:Biological Factors / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D009865:Oocytes; D016716:PC12 Cells; D018075:RNA, Complementary / Q000302:isolation & purification; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins; D014162:Transfection; D014982:Xenopus laevis
D016564:Amyloid beta-Protein Precursor; D001685:Biological Factors; D017077:Culture Media, Conditioned; C473649:NR1A NMDA receptor, rat; C121001:NR2B NMDA receptor; D018075:RNA, Complementary; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins