The mammalian brain is an immensely complex organ in terms of diversity of resident cell types, anatomical organization, neuronal circuitry, modes of intercellular communication, and the regulation of protein expression. Further the effect aging and Alzheimer's disease (AD) has on the brain represents a colossal challenge for researchers. Previous mass spectrometry based proteomic technologies have been most adept at identifying protein-protein interactions or post-translational modifications of enriched proteins from a single cell type. The recent development of in vivo isotopic labeling of mammals and high resolution mass spectrometers has afforded the opportunity to determine the relative protein expression level of thousands of proteins from tissue.
We aim to calculate changes in protein expression during Alzheimer's disease progression and regular aging in the mammalian brain by quantitative mass spectrometry. This project will yield a large-scale anatomic inventory of protein expression on an unprecedented level which can be mined for years to come. These quantitative proteomic studies will serve as a hypothesis-generating machine that will likely uncover new and unexpected data on the effect aging and AD have on the brain. Those in the advanced stages of AD become bed-bound and reliant on care 24/7 which in total results in 148 billion dollars in annual costs in the US alone. The effect of aging and AD on brain physiology has been historically investigated in candidate-based approaches. While these candidate approaches have significantly contributed to our understanding of aging and AD, they have been limited by their restricted scope. To broaden our knowledge base of these processes and eventually develop effective therapeutics for the treatment of AD we will calculate the expression level for thousands of proteins. Proteins with perturbed expression will serve as beacons for the identification of pathways relevant to AD pathology and aging. Determination of perturbed pathway(s) will in turn serve as fertile ground for in-depth analysis aimed at deciphering the molecular basis of AD and aging. More generally, this project will deliver a brain atlas of protein expression that occurs during aging and AD. AD represents a significant threat to the aging world population: AD is considered the world's most common neurodegenerative disease, affecting over 5 million aging Americans, and is a rising threat to public health. AD debilitates individuals by stripping them of the ability to reason, use language, and recall memories, resulting in a tremendous caretaking burden. Currently there is no cure or definitive treatment for AD and it remains the leading cause of dementia. AD is stratified by the age at which pathological onset occurs. The two forms of AD, early-onset and late-onset, both have genetic links. Identification of new genes and/or proteins that contribute to AD pathology could provide a critical first step for the development of effective AD treatments.

Public Health Relevance

Alzheimer's disease (AD) triples health care costs for those aged 65 or older and currently affects an estimated 5.3 million Americans. Here, we propose to complete the first large-scale anatomic inventory of protein expression during aging and AD progression. These studies should yield analysis at an unprecedented level and, through doing so, reveal novel pathways relevant to the successful treatment of this devastating disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Postdoctoral Individual National Research Service Award (F32)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-F01-L (20))
Program Officer
Refolo, Lorenzo
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
Wortham, Matthew; Benthuysen, Jacqueline R; Wallace, Martina et al. (2018) Integrated In Vivo Quantitative Proteomics and Nutrient Tracing Reveals Age-Related Metabolic Rewiring of Pancreatic ? Cell Function. Cell Rep 25:2904-2918.e8
Widjaja, Christella E; Olvera, Jocelyn G; Metz, Patrick J et al. (2017) Proteasome activity regulates CD8+ T lymphocyte metabolism and fate specification. J Clin Invest 127:3609-3623
Savas, Jeffrey N; Wang, Yi-Zhi; DeNardo, Laura A et al. (2017) Amyloid Accumulation Drives Proteome-wide Alterations in Mouse Models of Alzheimer's Disease-like Pathology. Cell Rep 21:2614-2627
Shrestha, Elina; Hussein, Maryem A; Savas, Jeffery N et al. (2016) Poly(ADP-ribose) Polymerase 1 Represses Liver X Receptor-mediated ABCA1 Expression and Cholesterol Efflux in Macrophages. J Biol Chem 291:11172-84
Yonashiro, Ryo; Tahara, Erich B; Bengtson, Mario H et al. (2016) The Rqc2/Tae2 subunit of the ribosome-associated quality control (RQC) complex marks ribosome-stalled nascent polypeptide chains for aggregation. Elife 5:e11794
Mita, Paolo; Savas, Jeffrey N; Briggs, Erica M et al. (2016) URI Regulates KAP1 Phosphorylation and Transcriptional Repression via PP2A Phosphatase in Prostate Cancer Cells. J Biol Chem 291:25516-25528
Brennand, K; Savas, J N; Kim, Y et al. (2015) Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Mol Psychiatry 20:361-8
Savas, Jeffrey N; Ribeiro, Luís F; Wierda, Keimpe D et al. (2015) The Sorting Receptor SorCS1 Regulates Trafficking of Neurexin and AMPA Receptors. Neuron 87:764-80
Shanks, Natalie F; Cais, Ondrej; Maruo, Tomohiko et al. (2014) Molecular dissection of the interaction between the AMPA receptor and cornichon homolog-3. J Neurosci 34:12104-20
Karttunen, Heidi; Savas, Jeffrey N; McKinney, Caleb et al. (2014) Co-opting the Fanconi anemia genomic stability pathway enables herpesvirus DNA synthesis and productive growth. Mol Cell 55:111-22

Showing the most recent 10 out of 21 publications