Decreasing the production of Abeta may be beneficial in the treatment of Alzheimer's Disease (AD). Basic research carried out through Projects 1 and 2 previously identified that allosteric modulators of gamma- secretase selectively lower Abeta42, without affecting Notch processing, and screened several Nonsteriodal anti-inflammatory drugs (NSAIDS) as candidates. We designed and conducted'a clinical trial to determine :he safety, tolerability and pharmacokinetics of R-flurbiprofen in healthy older adults. The data was used by Myriad Pharmaceuticals, Inc.,to plan and implement phase 2 and an ongoing program of phase 3 clinical trials of R-flurbiprofen in AD. In this renewal of Project 3, we aim to optimize biomarker measurements of Abeta in CSF to characterize Abeta lowering effects of R-flurbiprofen. We also aim to test ibuprofen, an NSAID with gamma-secretase modulating activity and anti-inflammatory actions, by carrying out a controlled clinical trial in patients with amnestic Mild Cognitive Impairment (aMCI), the earliest clinically diagnosable stage of AD. This targets early intervention, before patients have developed extensive amyloid deposition and damage to neurons and synapses. We hypothesize that lowering Abeta42 very early in AD may have beneficial effects on imaging and biochemical biomarkers. We have 2 aims: (1) To evaluate CSF levels of Abeta42 after acute treatment with R-flurbiprofen at a high dose of 1600mg in healthy adults, using a lumbar CSF catheter to obtain CSF samples during 24 hours, and the technique of stable isotopic labeling to calculate Abeta synthesis rates. This will characterize the timing and duration of Abeta lowering actions. (2) To evaluate biomarker changes in CSF and brain atrophy measures on MRI,in 100 patients with aMCI who will be randomized to treatment with ibuprofen 800 mg three times per day (+ omeprazole 20 mg/day for gastroprotection), or to placebo, for 12 months. CSF and MRI will be obtained at baseline and 12 months and a brief neuropsychological test battery (NTB) and lADL-questionnaire will be given at baseline, 6 and 12 months. Primary outcome measures will be change in hippocampal and total brain volume (MRI); concentrations of total tau, phosphotau 181,Abeta42 and Abeta38, and F2-isoprostanes (CSF). Secondary outcome measures will be change in NTB and ADCS ADL-MCI scores. Significance: No treatment has been shown to have disease-modifying effects in AD. CSF biomarkers and MRI measures allow us to monitor whether treatment that targets modulation of gamma-secretase will (1) selectively lower Abeta42 in humans following acute treatment;(2) have beneficial effects on biomarkers related to Abeta and to damage from the resulting cascade of pathology in aMCI, the earliest clinical stage at which AD can be diagnosed. These results will support further efforts to develop gamma-secretase modulators for early clinical use.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG020206-10
Application #
8497562
Study Section
Special Emphasis Panel (ZAG1-ZIJ-3)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
10
Fiscal Year
2013
Total Cost
$559,314
Indirect Cost
$44,595
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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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
Ran, Yong; Cruz, Pedro E; Ladd, Thomas B et al. (2014) ?-Secretase processing and effects of ?-secretase inhibitors and modulators on long A? peptides in cells. J Biol Chem 289:3276-87

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