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Regulation of Cytokine Secretion and Amyloid Precursor Protein Processing by Proinflammatory Amyloid Beta (Aβ)
Author(s) -
GITTER BRUCE D.,
BOGGS LEONARD N.,
MAY PATRICK C.,
CZILLI DAN L.,
CARLSON CHRISTOPHER D.
Publication year - 2000
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2000.tb05379.x
Subject(s) - amyloid precursor protein , proinflammatory cytokine , amyloid beta , neuroprotection , secretion , beta (programming language) , neurotrophin , neurodegeneration , p3 peptide , endocrinology , cytokine , chemistry , medicine , alzheimer's disease , biology , biochemistry , peptide , inflammation , receptor , disease , computer science , programming language
A bstract : Neurodegenerative processes in Alzheimer's disease (AD) are thought to be driven, in part, by the deposition of amyloid beta (Aβ), a 39‐43‐aminoacid peptide product resulting from an alternative cleavage of amyloid precursor protein (APP). In addition to its neurotoxic properties, Aβ may influence neuropathology by stimulating glial cell cytokine and acute phase protein secretion in affected areas of the brain (e.g., cortex, hippocampus). Using an in vitro human astrocyte model (U‐373 MG astrocytoma cells), the effects of Aβ treatment on acute phase protein (APP and alpha‐1‐antichymot rypsin [α 1 ‐ACT]) and interleukin‐8 (IL‐8) were examined. U‐373 MG cells secreted increased levels of α 1 ‐ACT and neurotrophic/neuroprotective alpha‐cleaved APP (αAPP) after exposure to interleukin‐1β (IL‐1β) for 24 hours. Aβ treatment resulted in a similar, but modest increase in α 1 ‐ACT secretion, a two‐ to threefold stimulation of IL‐8 production, and, conversely, a profound reduction in the levels of secreted αAPPs. Aβ inhibited αAPP secretion by U‐373 MG cells in a concentration‐ and conformation‐dependent manner. Moreover, the reduction in αAPP secretion was accompanied by an increase in cell‐associated APP. Another proinflammatory amyloidogenic peptide, human amylin, similarly affected APP processing in U‐373 astrocytoma cells. These data suggest that Aβ may contribute to Alzheimer's‐associated neuropathology by lowering the production of neuroprotective/neurotrophic αAPPs. Moreover, the concomitant increase in cell‐associated APP may provide increased substrate for the generation of amyloidogenic peptides within astrocytes.