The amyloid hypothesis states that altered Abeta production or clearance leading to gradual accumulation of aggregated Abeta, which in turn initiates the cascade of events leading to Alzheimer's disease. Increasing evidence supports the concept that the highly amyloidogenic Abeta42 isoform is the pathogenic species. Consequently, selective targeting of Abeta42 may be an excellent anti-amyloid strategy for Alzheimer's therapeutics. In the current funding cycle, we have reported that a subset of nonsteroidal anti-inflammatory drugs (NSAIDs) selectively lower Abeta42 while increasing shorter Abeta species without altering overall Abeta levels, an activity which we term gamma-secretase modulating action. Further, these findings led us io hypothesize that this activity may in part explain the apparent AD risk reduction in chronic users of NSAIDs. Thus, NSAIDs represent the prototypic members of a class of gamma-secretase modulators [GSM) that selectively lower Abeta42 in vitro and in vivo. We also provided preliminary characterization of its potential mechanism of action, which we now believe is centered on the gamma-secretase complex itself, including the APR substrate. In the next funding cycle, we hypothesize that this gamma-secretase modulating activity may target the initial epsilon-cleavage site, which appears to precede and possibly predict the cleavage of various Abeta peptides at the gamma-site. We will test this hypothesis in cultured cells and with in vitro membrane preparations. Further, in studies in collaboration with Project 2, we will examine the biology of shorter Abeta peptides that are invariably increased by Abeta42 lowering agents. We will ask whether shorter Abeta peptides are neurotoxic and whether they modulate the toxicity and aggregability of Abeta42 peptide by testing synaptic transmission and synaptic plasticity following exposure to these peptides. Finally, we will test whether combination treatments with Abeta42 lowering GSMs and a second unrelated compound are superior to treatment with single agents in reducing amyloid levels and amyloid associated pathology in APP transgenic mice. We hypothesize that targeting multiple cellular pathways will ultimately be more efficacious than single targets. We hope that our studies will be translated to testing in AD subjects in the future if we can demonstrate synergy with combination treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG020206-10
Application #
8497560
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
$354,127
Indirect Cost
$79,825
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Ling, I-Fang; Golde, Todd E; Galasko, Douglas R et al. (2015) Modulation of Aβ42 in vivo by γ-secretase modulator in primates and humans. Alzheimers Res Ther 7:55
Park, Hyo-Jin; Ran, Yong; Jung, Joo In et al. (2015) The stress response neuropeptide CRF increases amyloid-β production by regulating γ-secretase activity. EMBO J 34:1674-86
Jung, Joo In; Price, Ashleigh R; Ladd, Thomas B et al. (2015) Cholestenoic acid, an endogenous cholesterol metabolite, is a potent γ-secretase modulator. Mol Neurodegener 10:29
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
Lessard, Christian B; Cottrell, Barbara A; Maruyama, Hiroko et al. (2015) γ-Secretase Modulators and APH1 Isoforms Modulate γ-Secretase Cleavage but Not Position of ε-Cleavage of the Amyloid Precursor Protein (APP). PLoS One 10:e0144758
Ran, Yong; Ladd, Gabriela Z; Ceballos-Diaz, Carolina et al. (2015) Differential Inhibition of Signal Peptide Peptidase Family Members by Established γ-Secretase Inhibitors. PLoS One 10:e0128619
Ran, Yong; Cruz, Pedro E; Ladd, Thomas B et al. (2014) γ-Secretase processing and effects of γ-secretase inhibitors and modulators on long Aβ peptides in cells. J Biol Chem 289:3276-87
Chiang, Karen; Koo, Edward H (2014) Emerging therapeutics for Alzheimer's disease. Annu Rev Pharmacol Toxicol 54:381-405
Jung, Joo In; Ran, Yong; Cruz, Pedro E et al. (2014) Complex relationships between substrate sequence and sensitivity to alterations in γ-secretase processivity induced by γ-secretase modulators. Biochemistry 53:1947-57
Chu, Jin; Li, Jian-Guo; Ceballos-Diaz, Carolina et al. (2013) The influence of 5-lipoxygenase on Alzheimer's disease-related tau pathology: in vivo and in vitro evidence. Biol Psychiatry 74:321-8

Showing the most recent 10 out of 32 publications