Many Alzheimer’s drugs that looked promising in animal and cell culture studies have failed in clinical trials. A paper in the December 17 Stem Cell Reports proposes a new explanation for one such class of drugs, namely γ-secretase modulators (GSMs) derived from nonsteroidal anti-inflammatory drugs (NSAIDs). Researchers led by Philipp Koch at the University of Bonn, Germany, found that these compounds failed to lower Aβ42 in human neurons when added at concentrations comparable to those achieved in human trials. By contrast, at these same concentrations the drugs robustly suppressed Aβ42 production in rodent and human cell lines typically used in preclinical studies. The data, published online December 5, highlight the importance of testing AD drugs in human neurons, the authors suggest. It is unclear if the findings have any relevance for the second-generation GSMs now under investigation. These drugs are as much as 1,000 times more potent than the NSAID derivatives, and have a different mechanism of action (see Sep 2011 news story; Kretner et al., 2011; Borgegard et al., 2012).
“This is an important paper that highlights the need to develop human cell models to study AD,” Lawrence Rajendran at the University of Zurich wrote to Alzforum. He was not involved in the work. The study hints that γ-secretase might be regulated or localized differently in distinct cell populations, he suggested.
NSAID-based GSMs effectively lowered Aβ42 in preclinical studies both in vitro and in vivo, but Phase 2 and 3 trials were negative (see, e.g., Aug 2008 conference story; Vellas 2010). Because these compounds poorly enter the brain, researchers concluded that not enough of the drug reached its target.
Koch wondered if the target cell population might also play a role. To test this idea, first author Jerome Mertens generated human neuronal cultures from induced pluripotent stem cells made from fibroblasts of two familial AD patients and three controls (see image below). As expected, the AD neurons had higher ratios of secreted Aβ42/Aβ40 than did control cells. Addition of the high dose of 200 μM of four different NSAID-based GSMs (flurbiprofen, indometacin, diclofenac, and ibuprofen) cut this ratio by 25 percent or more in both AD and control neurons, showing that the drugs worked. However, in people these compounds are estimated to reach only the low micromolar range in the brain (see Bannwarth et al., 1990; Galasko et al., 2007). At these more realistic concentrations ranging from 1 to 80 μM, the authors saw no effect on secreted Aβ. By contrast, at these concentrations the GSMs squelched the Aβ42/Aβ40 ratio by around 50 percent in APP-overexpressing cell lines made from Chinese hamster ovaries and human embryonic kidney.
The findings show that, compared to other cell types, human neurons resist the effects of first-generation GSMs. The mechanism remains unclear. The authors did not test whether mouse neurons were also insensitive to these drugs. There is conflicting literature on this, with early pharmaceutical studies showing benefits in transgenic mouse models, while other studies have found little effect on Aβ in rodent brain and neuronal cultures (see Lanz et al., 2005; Stock et al., 2006; Carreras et al., 2013).—Madolyn Bowman Rogers
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