Amyloid beta plaque-associated proteins C1q and SAP enhance the Abeta1-42 peptide-induced cytokine secretion by adult human microglia in vitro.
Pro-inflammatory cytokines released by activated microglia could be a driving force in Alzheimer's disease (AD) pathology. We evaluated whether the presence of complement factor C1q and serum amyloid P component (SAP) in Abeta deposits is related to microglial activation. Activated microglia accumulate in SAP- and C1q-immunoreactive fibrillar amyloid beta (Abeta) plaques in AD temporal cortex. No clustered microglia are seen in SAP- and C1q-positive circumscript, non-fibrillar, tau-negative Abeta plaques in AD caudate nucleus and non-demented control temporal cortex. In addition, no clustered microglia were observed in C1q- and SAP-negative, irregular shaped, diffuse plaques in AD caudate nucleus and in non-demented control temporal cortex, which suggests that microglia are attracted and activated in Abeta deposits of certain fibrillarity that, in addition, have fixed SAP and C1q. Therefore, the effects of Abeta(1-42), SAP and C1q on cytokine secretion by human postmortem microglia in vitro were assessed. Abeta(1-42) alone had little to no effect. Abeta(1-42) peptides in combination with C1q or C1q and SAP increased microglial interleukin (IL)-6 secretion four- and eightfold, respectively. Tumor necrosis factor (TNF)-alpha, as well as intracellular IL-1alpha and IL-1beta levels, also increased upon exposure of microglia to Abeta(1-42)-SAP-C1q complexes. Combined with earlier findings, that amyloid and activated microglia accumulate at a relatively early stage of cognitive decline in AD patients, this suggests that clustering of activated, cytokine-secreting microglia in SAP- and C1q-containing Abeta deposits precedes neurodegenerative changes in AD, and thus may provide a "therapeutic window".
Veerhuis
Robert
R
Department of Pathology, Research Institute Neurosciences Vrije Universiteit, Vrije Universiteit medical center, DeBoelelaan 1117, 1081 HV Amsterdam, The Netherlands. r.veerhuis@vumc.nl
Van Breemen
Mariëlle J
MJ
Hoozemans
Jeroen M
JM
Morbin
Michela
M
Ouladhadj
Jamal
J
Tagliavini
Fabrizio
F
Eikelenboom
Piet
P
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D002478:Cells, Cultured; D015922:Complement C1q / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D017628:Microglia / Q000166:cytology / Q000378:metabolism*; D008854:Microscopy, Electron; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D000683:Serum Amyloid P-Component / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016207:Cytokines; D010446:Peptide Fragments; D000683:Serum Amyloid P-Component; C075222:amyloid beta-protein (1-42); D015922:Complement C1q