# Assessing cellular aging in old and rejuvenated neurons from Alzheimer patients

> **NIH NIH R01** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2020 · $485,000

## Abstract

SUMMARY
 Pathogenesis of Alzheimer’s disease ( 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.

## Key facts

- **NIH application ID:** 9926786
- **Project number:** 5R01AG056306-04
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** FRED H GAGE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $485,000
- **Award type:** 5
- **Project period:** 2017-07-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926786

## Citation

> US National Institutes of Health, RePORTER application 9926786, Assessing cellular aging in old and rejuvenated neurons from Alzheimer patients (5R01AG056306-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9926786. Licensed CC0.

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