Pathogenesis of A l z h e i m e r ? s d i s e a s e ( AD) is highly age-related and prevalence increases exponentially after the age of 60. While at the age of 70 around 5% of all people are affected, more than one third over the age of 85 are afflicted with AD. In addition to the dramatic increase seen in patients suffering from age-related neurodegenerative disorders in industrialized countries, a substantial increase in AD patients in the developing world is also observed in tandem with their aging populations. Currently, there are no treatments available for AD that could slow, halt or reverse the progression of the disease. This growing problem can only be mitigated if we can gain a more complete understanding of AD pathogenesis, which obviously demands a solid understanding of human biological aging. This project proposed by Dr. Gage and colleagues will, for the first time, challenge the importance of cellular aging in a human model for the disease. The Gage lab has recently shown that direct conversion of human fibroblasts into induced neurons (iNs) preserves signatures of cell aging, allowing the detection of cellular pathologies relevant to human aging. By contrast, induced pluripotent stem cell (iPSC) reprogramming erases age-dependent differences; iPSC-derived neurons thus resemble rejuvenated cells. To better understand the impact of neuronal cell aging on the pathology of sporadic AD, the first aim of this group is to generate both phenotypically old and rejuvenated neurons from a large set of clinically well-characterized AD patients and matched controls. Following an unbiased transcriptome approach, they will analyze for AD-specific gene expression profiles and work to understand which of the AD-specific gene expression signatures and related mechanisms are age-dependent and which are age-independent. Dysregulation of nucleo-cytoplasmic transport and the import receptor RanBP17 are currently emerging as major topics in aging and neurodegenerative disease research. In their second aim, Dr. Gage's team will work to identify the binding partners and exact functions of the yet understudied protein RanBP17. In a third aim, they will harness their recently established reporter system to measure nucleo- cytoplasmic compartmentalization in young and old AD neurons and probe for nuclear transport-based mediators of age-dependent AD pathology using live cell imaging approaches. Age-dependent accumulation of DNA damage contributes to genetic diversity among our cells, a process known as somatic mosaicism. As recent evidence suggests that AD only needs a small seed from which the pathology can spread throughout the brain, somatic mosaicism might play an important role in the development of sporadic AD. In a fourth aim, the Gage team will use simultaneous DNA and RNA sequencing of single post-mortem neurons and iNs from the same patients and ask to what extent DNA copy number variations can turn a neuron into a potential `AD seed' cell.

Public Health Relevance

The project by Dr. Gage and colleagues aims at deciphering the molecular and cell biological impact of human aging on Alzheimer's disease patient-specific induced neurons (iNs) and their rejuvenated counterparts (iPSC-iNs). The Gage lab will employ unbiased transcriptome approaches to analyze a clinically well-defined cohort of over 30 patient and control samples. They will further study age-dependent nuclear pore defects in the AD neurons and assess the involvement of aging-associated somatic mosaicism in post-mortem and reprogrammed neurons from the same patients.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG056306-01
Application #
9361030
Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Wise, Bradley C
Project Start
2017-07-15
Project End
2022-04-30
Budget Start
2017-07-15
Budget End
2018-04-30
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Eftekharzadeh, Bahareh; Daigle, J Gavin; Kapinos, Larisa E et al. (2018) Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer's Disease. Neuron 99:925-940.e7
Mertens, Jerome; Marchetto, Maria C; Bardy, Cedric et al. (2016) Evaluating cell reprogramming, differentiation and conversion technologies in neuroscience. Nat Rev Neurosci 17:424-37