Ibuprofen suppresses interleukin-1beta induction of pro-amyloidogenic alpha1-antichymotrypsin to ameliorate beta-amyloid (Abeta) pathology in Alzheimer's models.
Epidemiological and basic research suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) should protect against the most common forms of Alzheimer's disease (AD). Ibuprofen reduces amyloid (Abeta) pathology in some transgenic models, but the precise mechanisms remain unclear. Although some reports show select NSAIDs inhibit amyloid production in vitro, the possibility that in vivo suppression of amyloid pathology occurs independent of Abeta production has not been ruled out. We show that ibuprofen reduced Abeta brain levels in rats from exogenously infused Abeta in the absence of altered Abeta production. To determine whether ibuprofen inhibits pro-amyloidogenic factors, APPsw (Tg2576) mice were treated with ibuprofen for 6 months, and expression levels of the Abeta and inflammation-related molecules alpha1 antichymotrypsin (ACT), apoE, BACE1, and peroxisome proliferator-activated receptor gamma) (PPARgamma) were measured. Among these, ACT, a factor whose overexpression accelerates amyloid pathology, was reduced by ibuprofen both in vivo and in vitro. IL-1beta, which was reduced in our animals by ibuprofen, induced mouse ACT in vitro. While some NSAIDs may inhibit Abeta42 production, these observations suggest that ibuprofen reduction of Abeta pathology may not be mediated by altered Abeta42 production. We present evidence supporting the hypothesis that ibuprofen-dependent amyloid reduction is mediated by inhibition of an alternate pathway (IL-1beta and its downstream target ACT).
Morihara
Takashi
T
Greater Los Angeles VA Healthcare System, GRECC, Sepulveda, CA, USA.
Teter
Bruce
B
Yang
Fusheng
F
Lim
Giselle P
GP
Boudinot
Sally
S
Boudinot
F Douglas
FD
Frautschy
Sally A
SA
Cole
Greg M
GM
D000209:Acute-Phase Proteins / Q000378:metabolism; D000544:Alzheimer Disease / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases; D000686:Amyloidosis / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000096:biosynthesis; D016282:Aspartic Acid Endopeptidases; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001254:Astrocytoma / Q000378:metabolism; D015153:Blotting, Western; D010450:Endopeptidases / Q000096:biosynthesis; D007052:Ibuprofen / Q000494:pharmacology*; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009457:Neuroglia / Q000187:drug effects; D058225:Plaque, Amyloid / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000514:alpha 1-Antichymotrypsin / Q000096:biosynthesis / Q000378:metabolism*
D000209:Acute-Phase Proteins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001057:Apolipoproteins E; D007375:Interleukin-1; D015842:Serine Proteinase Inhibitors; D000514:alpha 1-Antichymotrypsin; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D007052:Ibuprofen