# iPSC Modeling of AD Using Progerin

> **NIH NIH R01** · REGENERATIVE RESEARCH FOUNDATION · 2020 · $428,106

## 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 nucleo-cytoplasmic compartmentation, chromatin organization
and gene expression similar to the accumulation of the LMNA isoform progerin. We hypothesize that forced
expression of progerin accelerates age-associated changes and disease phenotypes in iPSC-cortical cells
derived from AD patients. In our studies using R406W MAPT isogenic pairs, progerin over expression caused
distorted nuclei, reduction in heterochromatin, increased DNA damage and a concomitant reduction in Lamin B1
in both neurons and astrocytes. In addition, R406W mutant derived cultures showed higher rate of cell death
and loss of synapses following progerin over expression. Synapse loss is a well-recognized feature of AD and
related dementias, and given the exacerbation of this with progerin treatment, we are focused on this important
observation. In order to study synapses effectively in the collection of patient-derived iPSC lines, we needed to
establish a cortical differentiation protocol in which synaptic markers appear robustly and earlier compared to
other protocols. We now propose to perform an in-depth transcriptomic and functional analysis of cortical cultures
generated with this new protocol. Using this improved in vitro synaptogenesis iPSC-cortical model, we will assess
and quantify the effects of forced progerin expression on cell phenotypes related to AD pathology, including A?
and tau secretion, aggregation and turnover, in iPSC-2D cortical cells and in 3D cortical organoids. We will also
assess the impact of introducing microglia into 3D organoids and study microglia mediated synapse loss. This
supplemental work to characterize and utilize the improved cortical synaptogenesis protocol will significantly
enhance our ability to model AD using progerin-induced accelerated aging. The findings will open new avenues
for investigating the contribution of ag...

## Key facts

- **NIH application ID:** 10048364
- **Project number:** 3R01AG056293-03S1
- **Recipient organization:** REGENERATIVE RESEARCH FOUNDATION
- **Principal Investigator:** SALLY TEMPLE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $428,106
- **Award type:** 3
- **Project period:** 2020-03-15 → 2021-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10048364

## Citation

> US National Institutes of Health, RePORTER application 10048364, iPSC Modeling of AD Using Progerin (3R01AG056293-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10048364. Licensed CC0.

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