# iPSC Modeling of AD Using Progerin

> **NIH NIH R01** · REGENERATIVE RESEARCH FOUNDATION · 2021 · $403,125

## Abstract

Project Summary/Abstract
Age is the strongest risk factor for Alzheimer's disease (AD). However, cell and animal models of AD fail to
recapitulate human aging and fail to capture key aspects of disease pathology. Our long-term goal is to
understand how aging contributes to AD pathogenesis. Therefore, we propose to develop an induced
pluripotent stem cell (iPSC)-based model of AD that incorporates accelerated aging, with the objective of more
robustly modeling AD onset and progression. Recent findings indicate that perturbations in lamin A biology
may contribute to AD. In preliminary studies, we have found a significant increase in LMNA, the gene that
encodes the nuclear envelope protein lamin A, and a significant decrease in ZMPSTE24, a prelamin A
processing enzyme, in autopsy-confirmed AD brain tissue and in laser-dissected neurons from AD brains
compared to age-matched controls. We predict that these changes in LMNA and ZMPSTE24 levels would
cause an increase in farnesylated prelamin A, which has been shown to drive accelerated aging phenotypes,
including acquisition of an abnormal nuclear lamina, and impairments in nucleocytoplasic compartmentation,
chromatin organization and gene expression similar to the accumulation of the LMNA isoform progerin. We
hypothesize that forced expression of prelamin A or progerin accelerates age-associated changes and disease
phenotypes in iPSC-cortical cells derived from AD patients. First, we will determine whether lamin A
expression and processing are perturbed in AD brains and AD-predisposed iPSC-cortical cells. We will then
determine whether forced progerin expression causes aging-related dysfunction in AD-predisposed iPSC-
cortical neurons and astrocytes. Finally, we will define and quantify the effects of forced progerin expression on
cell phenotypes related to AD pathology, including Aβ and tau secretion, aggregation and turnover, in iPSC-2D
cortical cells and in 3D forebrain organoids. The results from this study will determine whether perturbations in
lamin A biology are associated with AD, and potentially contribute to AD pathogenesis, and will establish a
novel model incorporating lamin A-related aging parameters in a human AD iPSC-cortical cell model. These
findings will open novel avenues for investigating the contribution of aging to the disease mechanisms
underlying AD pathology and will advance the development of in vitro models of AD to aid in the design and
validation of potential therapeutic strategies.

## Key facts

- **NIH application ID:** 10153610
- **Project number:** 5R01AG056293-05
- **Recipient organization:** REGENERATIVE RESEARCH FOUNDATION
- **Principal Investigator:** SALLY TEMPLE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $403,125
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10153610

## Citation

> US National Institutes of Health, RePORTER application 10153610, iPSC Modeling of AD Using Progerin (5R01AG056293-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10153610. Licensed CC0.

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