This proposal is for a five year renewal (years 6-10) of a Program Project to pursue gamma-secretase modulating compounds as Alzheimer's disease (AD) therapeutics at the University of California, San Diego, consortium with Mayo Clinic Jacksonville and Washington University, St Louis. In the first five years of support, we have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) have a novel secondary action that modulates gamma-secretase processing in a cyclooxygenase (COX) independent manner. The activity of a subset of NSAIDs preferentially lowers the amyloidogenic A?42 peptide both in vitro and in vivo, leading us to propose that this activity may be one explanation for the apparent risk reduction of AD in chronic NSAID users. As we have identified many compounds in addition to NSAIDs that shift gamma secretase cleavage, we now generically refer to these compounds as gamma-secretase modulators (GSMs). Our research efforts have contributed to the introduction of the first GSM, R-flurbiprofen (""""""""Flurizan"""""""" renamed Tarenflurbil"""""""") into the clinic for testing in AD treatment, and led to the preclinical development of additional GSMs. The two major goals of this PPG are to further understand the mechanism of action of GSMs, and to test their activity in humans as well as determine their ability to lower disease-associated biomarkers in AD individuals. Project 1 will examine the site of action of GSMs with respect to effects on gamma- versus epsilon-cleavage and test the efficacy of combination treatments in rodents. Project 2, which has now incorporated the former Chemistry Core, will extend studies relating to the binding site of multiple GSMs, examine the relative contribution of GSMs with respect to reducing A?42 production vs. inhibiting A? aggregation, and conduct animal studies to better define how GSMs acutely alter A? levels in the brain, CSF, and plasma of mouse AD models. Projects 1 and 2 will coordinately examine the biological properties of shorter A? peptides which are elevated by these GSMs. Project 3 will determine if R-flurbiprofen lowers A?42 in human CSF by measuring newly synthesized A? through in-dwelling catheter and will test whether a GSM (ibuprofen) will reduce disease associated CSF biomarkers and brain volumetric changes by neuroimaging in AD subjects in a one year placebo controlled double-blind treatment study. Successful completion of these studies will provide greater insight into 1) how the GSMs shift gamma cleavage, 2) how GSMs attenuate AD-like phenotypes in rodent models, and 3) how GSMs and GSM based NSAIDs may work in humans. By providing additional preclinical and clinical information on GAMs, such studies should contribute significantly to the further development of GSMs as Alzheimer's therapeutics.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Study Section
Special Emphasis Panel (ZAG1-ZIJ-3 (O3))
Program Officer
Refolo, Lorenzo
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Moore, Brenda D; Martin, Jason; de Mena, Lorena et al. (2018) Short A? peptides attenuate A?42 toxicity in vivo. J Exp Med 215:283-301
Ran, Yong; Hossain, Fokhrul; Pannuti, Antonio et al. (2017) ?-Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct. EMBO Mol Med 9:950-966
Park, Sun Ah; Chevallier, Nathalie; Tejwani, Karishma et al. (2016) Deficiency in either COX-1 or COX-2 genes does not affect amyloid beta protein burden in amyloid precursor protein transgenic mice. Biochem Biophys Res Commun 478:286-292
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Jung, Joo In; Price, Ashleigh R; Ladd, Thomas B et al. (2015) Cholestenoic acid, an endogenous cholesterol metabolite, is a potent ?-secretase modulator. Mol Neurodegener 10:29
Park, Hyo-Jin; Ran, Yong; Jung, Joo In et al. (2015) The stress response neuropeptide CRF increases amyloid-? production by regulating ?-secretase activity. EMBO J 34:1674-86
Nhan, Hoang S; Chiang, Karen; Koo, Edward H (2015) The multifaceted nature of amyloid precursor protein and its proteolytic fragments: friends and foes. Acta Neuropathol 129:1-19
Ran, Yong; Ladd, Gabriela Z; Ceballos-Diaz, Carolina et al. (2015) Differential Inhibition of Signal Peptide Peptidase Family Members by Established ?-Secretase Inhibitors. PLoS One 10:e0128619
Jung, Joo In; Ran, Yong; Cruz, Pedro E et al. (2014) Complex relationships between substrate sequence and sensitivity to alterations in ?-secretase processivity induced by ?-secretase modulators. Biochemistry 53:1947-57

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