# High Resolution Profiling of Senescent Neurons and Their Microenvironments in Postmortem Human Brain Tissue Spanning Eight Decades of Life

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2022 · $387,594

## Abstract

Project Summary/Abstract
Advanced chronological age is the greatest risk factor for developing Alzheimer’s disease. Accumulating
evidence suggests that disease processes may begin decades prior to dementia. Therefore, cellular and
molecular processes that contribute to biological aging may also modulate Alzheimer’s disease pathogenesis.
We recently identified a fundamental cellular aging stress response, cellular senescence, as a pathogenic
process driving neurodegeneration in tauopathies, brain diseases histologically defined by tau protein
accumulation. Features of cellular senescence include stable cell cycle arrest and toxic secretory phenotype.
In this way, senescent cells escape cell death and become persistently deleterious to their surrounding
environment. We have found a causal relationship connecting tau accumulation (i.e. neurofibrillary tangles),
a neuronal senescence-like phenotype, and chronic neurodegeneration in tauopathies, including Alzheimer’s
disease. As terminally differentiated cells, neurons may seem incapable of initiating a senescence stress
response. However, our data indicate that neurons with mature neurofibrillary tangles are arrested in a
cellular senescence-like state. The objective of this project is to identify the upstream molecular mediators
and downstream cellular consequences of neuronal senescence in the human brain. High resolution profiling
methods will be applied to analyze neurons across the adult human lifespan, and throughout the progressive
stages of Alzheimer’s disease. This project will significantly advance the basic understanding of this novel
neuronal cell fate, cellular senescence, and its influence on brain health. Moreover, the cellular and molecular
pathways identified in our project may reveal novel therapeutic targets for intervention, and the age/stage of
disease where they would be most beneficial.

## Key facts

- **NIH application ID:** 10414099
- **Project number:** 5R01AG068293-03
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Miranda Ethel Orr
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $387,594
- **Award type:** 5
- **Project period:** 2020-09-10 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10414099

## Citation

> US National Institutes of Health, RePORTER application 10414099, High Resolution Profiling of Senescent Neurons and Their Microenvironments in Postmortem Human Brain Tissue Spanning Eight Decades of Life (5R01AG068293-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10414099. Licensed CC0.

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