# Role of Cellular Senescence in the Bone-Brain Interplay

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $409,375

## Abstract

PROJECT SUMMARY/ABSTRACT
Alzheimer's disease (AD), the most common form of dementia, is closely associated with osteoporosis, another
age-associated bone disorder. It has been proposed that there is an interplay between skeletal and central
nervous system independent of age. However, the mechanistic link for the bone-brain interaction has been
largely overlooked and understudied. We recently found that old mice, relative to young mice, have reduced
blood vessel density and compromised blood-brain barrier (BBB) integrity in hippocampus, and our preliminary
data suggests that bone/bone marrow cells secreted cytokines/growth factors, which may contribute to these
age-associated brain vascular changes. Particularly, we detected accumulated senescent cells in bone/bone
marrow of old mice (vs. young mice) and AD mice (vs. wild-type mice). These senescent cells are primarily
bone/bone marrow mononuclear pre-osteoclasts (Pre-OCs), which acquire a unique SASP, with PDGF-BB as
the highest expressed factor. Importantly, serum PDGF-BB levels were markedly elevated in old animals (vs.
young animals) and AD mice (vs. control mice), and ablation of the Pre-OCs reduced serum PDGF-BB
concentration. Our results suggest that Pre-OCs in bone/bone marrow is a main source of elevated circulating
PDGF-BB during aging and AD progression. While PDGF-BB maintains the homeostasis of the cerebral
vasculature under physiological conditions, abnormally high concentration of PDGF-BB may lead to brain
vascular impairment. Indeed, we found that ablation of Pre-OCs attenuated age-associated cerebral vascular
impair. Our central hypothesis is that the senescent Pre-OCs in bone/bone marrow secrete excessive PDGF-
BB into blood circulation, leading to cerebral vascular impairment to accelerate brain aging and AD progression.
In Aim 1, we will determine the contribution of SnBCs to normal brain aging and AD progression using bone
marrow transplantation approach and genetic mice to induce Pre-OCs ablation. We will examine the changes of
brain pathologies and cognitive deficits during aging and AD progression. In Aim 2, we will determine the role of
PDGF-BB secreted by SnBCs in brain aging and AD progression by systemically administering a PDGF-BB
neutralizing antibody (Ab) and employing genetic mice to knock-out or knock-in PDGF-BB in Pre-OCs. We will
examine the changes of brain pathologies and cognitive deficits during aging and AD progression. Positive
findings in this study will provide new understanding on relationship between brain and bone in the development
of neurodegenerative disease and present an unconventional but promising path for early treatment of AD.

## Key facts

- **NIH application ID:** 10236355
- **Project number:** 5R01AG068226-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Mei Wan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $409,375
- **Award type:** 5
- **Project period:** 2020-08-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10236355

## Citation

> US National Institutes of Health, RePORTER application 10236355, Role of Cellular Senescence in the Bone-Brain Interplay (5R01AG068226-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10236355. Licensed CC0.

---

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