Lack of Specific Amyloid-β(1-42) Suppression by Nonsteroidal Anti-Inflammatory Drugs in Young, Plaque-Free Tg2576 Mice and in Guinea Pig Neuronal Cultures

Abstract

Recent studies indicating that some nonsteroidal anti-inflammatory drugs (NSAIDs) selectively modulate gamma-secretase cleavage of amyloid precursor protein (APP) while sparing Notch processing have generated interest in discovery of novel gamma-secretase modulators with the "NSAID-like" efficacy profile. The objective of the present studies was to compare the efficacy of a subset of NSAIDs with previously reported classical gamma-secretase inhibitors LY-411575 [N(2)-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N(1)-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide]and DAPT [N-[N- (3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester] in Tg2576 mice. Flurbiprofen (10 and 25 mg/kg/day) was overtly toxic and elicited significant (but nonselective) reductions in both Abeta(1-40) and Abeta(1-42) in the plasma in one of two studies. Flurbiprofen also produced a small reduction in Abeta(1-40) in the cortex at 25 mg/kg/day but did not affect Abeta levels in hippocampus or cerebrospinal fluid. Ibuprofen and sulindac sulfide were neither overtly toxic nor efficacious at doses up to 50 mg/kg/day. The effects of NSAIDs LY-411575 and DAPT were tested in guinea pig embryonic neuronal cultures to determine whether the selective reductions in Abeta(1-42) observed in cell lines overexpressing human mutant APP can be reproduced in a neuronal model of physiological Abeta production and secretion. Flurbiprofen and sulindac nonselectively reduced Abeta(1-40) and Abeta(1-42) at concentrations > or =125 microM, although cytotoxicity was noted at > or =250 microM sulindac. Ibuprofen had no effect at concentrations up to 500 microM. In contrast, DAPT and LY-411575 potently and completely inhibited Abeta(1-40), Abeta(1-42), and Abeta(1-38) in the absence of cytotoxicity. The divergence of the present data from published reports raises the need to examine the conditions necessary to perceive selective Abeta(1-42) reduction by NSAIDs in neuronal tissue.

1-(3′,4′-Dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-cyclopropanecarboxylic Acid (CHF5074), a Novel γ-Secretase Modulator, Reduces Brain β-Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease without Causing Peripheral Toxicity

“…These brain concentrations are not higher than those attained in young transgenic Tg2576 mice after short-term treatment (10.2 Ϯ 3.7 M, after 100 mg/kg/day for 4 days) where we failed to demonstrate a decrease in brain A␤ levels (Imbimbo et al, 2007). This is in line with previous reports indicating that short-term administration (3-8 days) of A␤-lowering NSAIDs in young Tg2576 transgenic mice does not attain significant effects on brain A␤ levels (Lanz et al, 2005;Peretto et al, 2005;Stock et al, 2006). Alternatively, long-term treatments (3-8 months) with ibuprofen (Lim et al, 2000(Lim et al, , 2001Yan et al, 2003) indomethacin (Sung et al, 2004), or flurbiprofen derivatives (Jantzen et al, 2002;van Groen et al, 2005;Wilcock et al, 2007) have shown a significant reduction in brain A␤ pathology in transgenic mice.…”

A Novel Phospholipid Derivative of Indomethacin, DP-155 [Mixture of 1-Steroyl and 1-Palmitoyl-2-{6-[1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetamido]hexanoyl}-sn-glycero-3-phosophatidyl Choline], Shows Superior Safety and Similar Efficacy in Reducing Brain Amyloid β in an Alzheimer's Disease Model

“…Weggen et al (2001) demonstrated that selective NSAIDs induce alteration of the ␥-secretase cleavage pattern, which leads to reduced production of A␤42, without affecting A␤40 levels. Selective reduction of A␤42 was also seen in our study but not in some other studies where non-indomethacin, ␥-secretase inhibitors were employed (Lanz et al, 2005). We used the same model and dosing paradigm (high doses for a very short period) reported by Weggen et al (2001) since it resulted in consistent reduction in A␤42.…”

NSAIDs prevent, but do not reverse, neuronal cell cycle reentry in a mouse model of Alzheimer disease

“…Third, NSAIDs may have off-target effects. Some studies have demonstrated that an acute, relatively shortterm administration of selected NSAIDs to AD mouse models results in decreased production of longer Aβ peptides, in favor of shorter, less-amyloidogenic isoforms (56), although not all studies have observed this effect (57). This would offer a potential nonimmune mechanism of NSAID action.…”