# Programming age in iPS models of Alzheimer's disease

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $449,000

## Abstract

Project Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disorder in humans. Despite several decades
of intense research there are currently still no effective treatments for AD. There has been considerable interest
in exploring the use of induced pluripotent stem cells (iPSCs) as a novel tool to study AD, as the technology can
capture the precise genetic background of a given AD patient. Furthermore, it is now possible to generate large
numbers of such patient-specific, human iPSC-derived neurons on demand. This represents a powerful tool to
study AD disease mechanisms in vitro, and to develop and test novel candidate therapies using iPSC-based
screening assays. However, a problem that has plagued the iPSC field is the immature, fetal-like nature of the
resulting neurons that does not match the age-related characteristics of AD patients. Furthermore, any age-
related cellular markers that are present in primary cells from AD patients appear to be rejuvenated after
reprogramming back to pluripotency. To address those limitations, we have recently reported on strategies to
artificially trigger age-related marker expression in iPSC-derived neurons by manipulating pathways known to
cause premature aging. Furthermore, we have provided proof-of-concept for using such induced aging strategies
in iPSC models of Parkinson’s disease. Those “induced aging” strategies include the ectopic expression of
progerin, a mutant form of the nuclear lamina protein LMNA, and the shortening of telomeres prior to and during
neural differentiation. Additional candidate strategies reported by other labs include knockdown of the RanBP17
gene, a factor involved in nuclear/cytoplasmic transport and global loss of heterochromatin, an epigenetic cellular
change that triggers premature aging-like feature in fibroblast. The goal of the current study is to test current and
to develop novel induced aging strategies that may be particularly suitable to model AD. First, we aim to compare
several current induced aging strategies in AD-iPSC-derived cortical neurons to assess, side-by-side, their ability
to trigger age-related marker expression and AD-related biochemical and degenerative changes. To model the
AD-specific effects, we will use isogenic AD-iPSC lines, recently established, carrying mutations in APP(Swe)
and presenilin 1 (PSEN1(M146V). Second, we will identify and validate novel candidate induced aging strategies
of particular relevance in triggering degenerative phenotypes in AD- but not in control iPSC-derived neurons.
Third, we will use the most promising strategies from Aim 1 and Aim 2 to determine their ability to trigger disease
phenotypes in iPSC-derived cortical neurons derived from patients with sporadic AD. Sporadic AD patients
represent the most common form of the disease and have been particularly difficult to model using conventional
iPSC technology.
 The proposed study will address whether current or novel induced aging strategies can con...

## Key facts

- **NIH application ID:** 10134971
- **Project number:** 5R01AG056298-05
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** LORENZ P. STUDER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $449,000
- **Award type:** 5
- **Project period:** 2017-07-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134971

## Citation

> US National Institutes of Health, RePORTER application 10134971, Programming age in iPS models of Alzheimer's disease (5R01AG056298-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10134971. Licensed CC0.

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