Activation of NR1a/NR2B receptors by soluble factors from APP-stimulated monocyte-derived macrophages: Implications for the pathogenesis of Alzheimer's disease

Amyloid-β peptide (Aβ), 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 α-processing soluble amyloid precursor protein/p3 (αAPPs/p3) or β-processing APP/Aβ (βAPPs/Aβ). 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 αAPPs/p3- and βAPPs/Aβ-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 μM 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 μM). The αAPPs/p3- and βAPPs/Aβ-stimulated MCM placed in non-injected oocytes failed to generate inward current. These results demonstrate that APPs/Aβ-stimulated MCM directly activate NMDA receptor subtypes relevant in the pathogenesis of AD.