# AMYLOIDOGENIC INDUCTION OF CELLULAR SENESCENCE IN ALZHEIMER'S DISEASE

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $411,503

## Abstract

PROJECT SUMMARY
 Cellular senescence, one of the major hallmarks of aging, describes the sudden inability for cells to divide.
Senescent cells often accumulate with age, in response to physical and chemical stressors (genomic instability,
telomere attrition, irradiation, etc.), though the overlap between these stressors and neurological diseases such
as Alzheimer’s Disease (AD) is currently unknown. In-vitro experiments of senescence often utilize contrived
stressors such as hydrogen peroxide or radiation, that may not be physiologically relevant for age-related
diseases such as AD. Furthermore, the senescence phenotypes observed in vitro are likely not complete models
for what is occurring in dynamic biological systems.
 Soluble amyloid-beta oligomers (Aβo), an important hallmark in AD, have been shown to potently induce
senescence in a variety of brain cell types and environments, in contrast to fibrillar Ab. Aβo is thought to bind
membrane proteins and subsequently signal downstream aggregation of related amyloids such as tau. In fact,
the presence of endogenous Aβo is one of the strongest indicators of disease severity in AD models and
organisms, suggesting a link between AD and cellular senescence that is only beginning to be explored.
 In order to study this association, we propose to combine gold-standard techniques and single-cell omics
data in order to define heterogenous genetic and epigenetic signatures of senescence that are distinctly a
function of their induction type. Doing so will also produce robust signatures and biomarkers of senescence in
brain cells that can be utilized for the pathological phenotyping of human tissues. These measures will also allow
for the comparison of disparate senescent behaviors to help identify lab-derived amyloids that best resemble
patient-derived constructs. We will evaluate multiple lab-derived Aβo constructs, including those stabilized from
lipids located in predominantly diseased regions of the brain. Observations would be synergistically coupled with
solution biophysics experiments and molecular modeling, providing analogous structural data for each inducer
type. Taken together, these measurements will uniquely profile senescence in brain cells, define the degree of
overlap between endogenous senescence inducers and those reconstituted in the lab, and highlighting how AD
risk is modulated by cellular senescence.

## Key facts

- **NIH application ID:** 10456063
- **Project number:** 5R01AG068285-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** ANDREW D. MIRANKER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $411,503
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10456063

## Citation

> US National Institutes of Health, RePORTER application 10456063, AMYLOIDOGENIC INDUCTION OF CELLULAR SENESCENCE IN ALZHEIMER'S DISEASE (5R01AG068285-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10456063. Licensed CC0.

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