The prominent risk factor for Alzheimer's Disease (AD) is aging. Animal studies establish an intimate link between signaling pathways that regulate lifespan and processes that control cellular protein homeostasis, including insulin growth factor 1 receptor (DAF-2/IGF-1R) signaling, dietary restriction (DR) and mitochondria! electron transport chain perturbations. The overall goal of Project 2 is to study cellular aging or senescence in cell-based models that enable us to understand more clearly how aging affects the cell biology that can lead to loss of protein homeostasis control and the onset of AD.
In Aim 1, we hypothesize that aging fundamentally changes the processing of APP into Abeta. We will utilize established fibroblast cell-based aging models and we will develop neuronal cell-based aging models to first demonstrate that aging signaling pathways that control the lifespan of worms and mice also influence cellular lifespan in culture. We will then express APP in these cell-based aging models to discern whether the youthful control of protein homeostasis is lost upon aging of the cells and whether DAF-2/IGF-1R signaling and related pathways influencing aging will extend their lifespan and protect the cells from proteotoxicity, as has been observed in whole animal models including worms and mice. Biochemical and morphological approaches including western blotting, immunofluorescence (IF) and immunoelectron microscopy (IEM) will be used to follow the processing of APP into Abeta, the subcellular appearance of aggregates and their spatial and temporal correlation with proteotoxicity contributing to senescence and cell death.
In Aim 2 we will utilize the aging models to study the membrane trafficking pathways to explore the hypothesis that they function well in young cells yet appear to fail in old cells, in an effort to begin to understand how the expression of APP and its conversion into Abeta becomes toxic with aging in the context of its extensive intracellular processing and trafficking.
Aim 2 is distinguished from Aim 1 by the utilization of numerous known biological perturbants of membrane trafficking pathways in a systematic fashion to discern how these pathways influence the processing of APP into Abeta the subcellular appearance of aggregates and their spatial and temporal correlation with proteotoxicity in the context of aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG031097-05
Application #
8429428
Study Section
Special Emphasis Panel (ZAG1-ZIJ-8)
Project Start
Project End
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
5
Fiscal Year
2013
Total Cost
$348,598
Indirect Cost
$165,029
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Bamberger, Casimir; Martínez-Bartolomé, Salvador; Montgomery, Miranda et al. (2018) Deducing the presence of proteins and proteoforms in quantitative proteomics. Nat Commun 9:2320
Pankow, Sandra; Bamberger, Casimir; Calzolari, Diego et al. (2016) Deep interactome profiling of membrane proteins by co-interacting protein identification technology. Nat Protoc 11:2515-2528
Eleuteri, Simona; Di Giovanni, Saviana; Rockenstein, Edward et al. (2015) Novel therapeutic strategy for neurodegeneration by blocking A? seeding mediated aggregation in models of Alzheimer's disease. Neurobiol Dis 74:144-57
Pankow, Sandra; Bamberger, Casimir; Calzolari, Diego et al. (2015) ?F508 CFTR interactome remodelling promotes rescue of cystic fibrosis. Nature 528:510-6
Alvarez, Antón; Aleixandre, Manuel; Linares, Carlos et al. (2014) Apathy and APOE4 are associated with reduced BDNF levels in Alzheimer's disease. J Alzheimers Dis 42:1347-55
Baird, Nathan A; Douglas, Peter M; Simic, Milos S et al. (2014) HSF-1-mediated cytoskeletal integrity determines thermotolerance and life span. Science 346:360-3
Park, Sung Kyu Robin; Aslanian, Aaron; McClatchy, Daniel B et al. (2014) Census 2: isobaric labeling data analysis. Bioinformatics 30:2208-9
Koob, Andrew O; Shaked, Gideon M; Bender, Andreas et al. (2014) Neurogranin binds ?-synuclein in the human superior temporal cortex and interaction is decreased in Parkinson's disease. Brain Res 1591:102-10
Greiner, Erin R; Kelly, Jeffery W; Palhano, Fernando L (2014) Immunoprecipitation of amyloid fibrils by the use of an antibody that recognizes a generic epitope common to amyloid fibrils. PLoS One 9:e105433
Bamberger, Casimir; Pankow, Sandra; Park, Sung Kyu Robin et al. (2014) Interference-free proteome quantification with MS/MS-based isobaric isotopologue detection. J Proteome Res 13:1494-501

Showing the most recent 10 out of 57 publications