# The contribution of p16-expressing cells to tauopathy

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2021 · $397,500

## Abstract

Project Summary
 Advanced age is the main risk factor for most chronic human diseases, including tauopathies and Alz-
heimer's disease (AD). However the molecular mechanisms underlying the exponential increases later in life
remain largely unknown, impeding the development of interventions that prevent or attenuate disease. It has
been proposed that senescent cells, which accumulate with aging in many tissues and organs and at sites of
age-related pathologies, promote tissue dysfunction. AD is characterized by the accumulation of Aβ peptide-
containing plaques and aggregates of hyper-phosphorylated or misfolded tau. Cells with features reminiscent
of senescence have been observed in post mortem AD patient samples, however when these cells were ac-
quired in the disease process and their contribution to pathology is unknown. Senescent cells are not merely
residents of aged tissues, they develop a complex phenotype, termed the senescence-associated secretory
phenotype (SASP), in which they secrete numerous growth factors, cytokines, and proteases that disrupt the
architecture and functionality of neighboring cells in the tissue. The critical barrier to testing the idea that se-
nescence is implicated in AD in vivo has been the lack of a mouse model that allows for selective elimination of
senescent cells. We made use of a biomarker for senescence, p16Ink4a, to generate a novel transgene, INK-
ATTAC, which removes p16Ink4a-positive senescent cells upon administration of a synthetic drug. We have fo-
cused our studies firstly on understanding whether pathologic tau accumulation drives senescence in a tauopa-
thy mouse model. In preliminary studies using a mouse model expressing a mutated form of human tau, we
find that elimination of senescent cells prior to disease onset reduces neurofibrillary tangle deposition, neuro-
degeneration and memory loss. With these results in mind, we will test our central hypothesis that senescent
cells are causally implicated in tau pathology and that removal of senescent cells will have a profound disease-
attenuating impact. We propose three specific aims. In the first aim we will determine the identity of the cells
that senesce in this model as well as the kinetics of senescent cell accumulation. In the second aim, we will
determine the nature and consequences of the secretory phenotype of senescent cells in the brain of our tau
mutant model. In the third aim we will establish the therapeutic potential of senescent cell removal in tauopa-
thy, where treatment to remove senescent cells is started after disease is established. The overall impact of
this project is that it will critically test the untested hypothesis that senescent cells promote neurodegeneration,
address key fundamental questions about disease-related senescent cells, identify key components of the
SASP that promote tauopathy, and test the entirely novel concept of targeting senescent cells or key elements
of the SASP as a therapeutic strategy for tau...

## Key facts

- **NIH application ID:** 10135790
- **Project number:** 5R01AG053229-05
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Darren Baker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $397,500
- **Award type:** 5
- **Project period:** 2017-07-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135790

## Citation

> US National Institutes of Health, RePORTER application 10135790, The contribution of p16-expressing cells to tauopathy (5R01AG053229-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10135790. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*