Nonsteroidal anti-inflammatory drugs (NSAIDs) in Alzheimer`s disease: mechanism of action and therapeutic potential
Zusammenfassung der Projektergebnisse
Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder currently afflicting nearly 5 million individuals in the European region. Compelling evidence indicates that aberrant production and accumulation of amyloid β-peptides (Aβ) is a central event in the pathology of both familial and sporadic forms of Alzheimer’s disease (AD). The aspartyl protease γ-secretase is a prime drug target in AD as it catalyses the final step in the generation of Aβ peptides from the amyloid precursor protein (APP). Highly potent γ-secretase inhibitors (GSIs) have been developed, but preclinical and clinical studies have also revealed substantial mechanism-based toxicity of GSIs, which can be largely attributed to disruption of processing and function of the γ-secretase substrate NOTCH. We have shown that some non-steroidal anti-inflammatory drugs (NSAIDs) including ibuprofen can selectively lower production of the highly amyloidogenic Aβ42 peptide, which has been proposed to be the disease-causing agent in AD. Importantly, these Aβ42-lowering NSAIDs did not impair NOTCH processing and function. These findings suggested a novel explanation for epidemiological observations that chronic intake of NSAIDs lowers the risk of developing AD. More importantly, these compounds originated a new class of potential AD therapeutics that could provide a safer alternative to GSIs. Molecules with selective Aβ42-lowering activity that spare NOTCH processing are now known as γ-secretase modulators (GSMs). Observations from our group and others had supported the hypothesis that Aβ42-lowering NSAIDs and other GSMs act by direct modulation of γ-secretase activity, but the molecular details were far from resolved. Consequently, the major goal of the research project was to further define the mechanism of action and the molecular target of GSMs. We were able to demonstrate that the Aβ42-lowering activity of GSMs is not mediated by specific signaling pathways as previously suggested. Furthermore, we did not find evidence that NSAID-type GSMs stimulate the release of the neurotrophic extracellular domain of APP. Such an activity had been suggested as an alternative mechanism for the protective effects of NSAIDs in AD unrelated to the Aβ42- lowering GSM activity. In contrast, we observed that many mutations in presenilin-1 (PSEN1), which cause familial forms of AD with early-onset (eFAD) render cells in culture resistant to the Aβ42-lowering activity of GSMs. PSEN1 is a part of the γ-secretase multiprotein complex and seems to harbor the active site of the enzyme complex. Therefore, the attenuation of the GSM effect by PSEN mutations provides strong evidence that GSMs directly interact with the enzyme complex and modulate enzyme activity. PSEN1 mutations further diminished the effects of GSIs, and this was also observed in vivo in a mouse model of AD with transgenic expression of a PSEN1 mutation. Taken together, these results have important implications for the use of cell lines and animals models in drug discovery efforts aimed at γ-secretase, as they suggest that studies to evaluate the potency and efficacy of GSIs and GSMs could be confounded by the eFAD mutants expressed in many models of AD. Most importantly, these results also have relevance for clinical studies of GSIs and GSMs. Patients with eFAD, which comprise around 200.000 individuals in the US, constitute a unique population to conduct treatment or prevention trials with novel pharmaceuticals. Our findings indicate the necessity to evaluate potential differences in the efficacy of compounds targeting the γ-secretase complex in sporadic AD versus eFAD in future clinical trials. Another priority was the development of GSMs with improved pharmacological properties. Our synthetic efforts in collaboration with medicinal chemists have yielded a novel GSM with nanomolar potency and excellent brain permeability. We have further discovered compounds that combine GSM activity with activation of the peroxisome proliferator activated receptor γ (PPARγ). Activators of PPARγ are widely prescribed antidiabetic drugs. Importantly, individuals with type-2 diabetes have a two-fold increased risk to develop AD. We propose that small molecules with dual GSM/PPARγ activity could be a novel strategy for prevention of AD, in particular in patients with type 2 diabetes. In these individuals, dual-active molecules could ameliorate the deleterious effects associated with type 2 diabetes by activation of PPARγ, and further confront the elevated risk for AD by modulating γ-secretase activity and lowering Aβ42 levels in brain. In summary, we have significantly advanced the understanding of the mechanism of Aβ42-lowering NSAIDs and other GSMs. Our findings that PSEN mutations block the efficacy of GSIs and GSMs have critical implications for the clinical development of these compound classes. Finally, we have generated valuable novel tools to further probe the molecular details of GSM action, and to define their efficacy in mouse models of AD in follow-up studies.
Projektbezogene Publikationen (Auswahl)
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(2005). Diverse compounds mimic Alzheimer’s disease causing mutations by augmenting Aβ42 production. Nature Medicine: 11(6): 545-50
Kukar T, Murphy MP, Eriksen JL, Sagi SA, Weggen S, Smith TE, Ladd T, Khan MA, Beard J, Dodson M, Merit S, Ozols VV, Anastasiadis PZ, Das P, Fauq A, Koo EH, Golde TE
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(2006). Inhibitors of Rho-kinase (ROCK) modulate amyloid-β (Ab) secretion but lack selectivity for Aβ42. Journal of Neurochemistry: 96(2): 355-65
Leuchtenberger S, Kummer M, Kukar T, Czirr E, Teusch N, Sagi SA, Berdeaux R, Pietrzik CU, Luc Mercken, Ladd TB, Golde TE, Koo EH, and Weggen S
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(2006). Selective modulation of Aβ42 production in Alzheimer‘s disease: non-steroidal anti-inflammatory drugs and beyond. Current Pharmaceutical Design, 12: 4337-55
Leuchtenberger S, Beher D, and Weggen S
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(2006). γ-Secretase modulation with Aβ42-lowering non-steroidal anti-inflammatory drugs and derived compounds. Neurodegenerative Diseases, 3: 298-304
Czirr E and Weggen S
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(2007). Insensitivity to Aβ42-lowering non-steroidal anti-inflammatory drugs (NSAIDs) and γ-secretase inhibitors is common among aggressive presenilin-1 (PS1) mutations. Journal of Biological Chemistry: 282(34): 24504-13
Czirr E, Leuchtenberger S, Dorner-Ciossek C, Schneider A, Jucker M, Koo EH, Pietrzik CU, Baumann KH, and Weggen S
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(2007). NSAIDs: small molecules for prevention of Alzheimer’s disease or precursors for future drug development? Trends In Pharmacological Sciences: 28: 536- 43
Weggen S, Rogers M, and Eriksen JL
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(2008). Curcumin derived pyrazoles and oxazoles–swiss knives or dirty tools for Alzheimer´s disease? ChemMedChem: 3(1): 165-72
Narlawar R, Pickhardt M, Leuchtenberger S, Baumann K, Weggen S, Mandelkow E, Schmidt B
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(2008). Independent generation of Aβ42 and Aβ38 peptide species by γ-secretase. Journal of Biological Chemistry: 283(25): 17049-54
Czirr E, Cottrell BA, Leuchtenberger S, Kukar T, Ladd TV, Esselmann H, Paul S, Schubenel R, Torpey JW, Pietrzik CU, Golde TE, Wiltfang J, Baumann KH, Koo EH, Weggen S
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(2008). Non-steroidal anti-inflammatory drugs (NSAIDs) and derived Aβ42-lowering molecules for treatment and prevention of Alzheimer’s disease. Pharmacological mechanisms in Alzheimer’s therapeutics: 167-93, Springer Science + Business Media, New York, USA
Weggen S, Czirr E, Leuchtenberger S, and Eriksen JL
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(2009). Non-steroidal anti-inflammatory drugs (NSAIDs) and ectodomain shedding of the amyloid precursor protein (APP). Neurodegenerative Diseases, 6: 1-8
Leuchtenberger S, Maler J, Czirr E, Ness J, Lichtenthaler S, Pietrzik C, Wiltfang J, and Weggen S
