# Impact of acid ceramidase activity on MIF-mediated migration of circulating osteoclast precursors to periodontal bone lesions in relation to aging

> **NIH NIH R01** · NOVA SOUTHEASTERN UNIVERSITY · 2021 · $380,000

## Abstract

ABSTRACT
This application will investigate the novel pathogenic host-bacterial interactions of which microglial-associated
neuroinflammatory hallmarks of Late Onset Alzheimer’s disease (LOAD) emerges with periodontitis in relation
to aging. The emerging evidence indicates that ligation of lipopolysaccharide (LPS) produced by the key
periodontal pathogen Porphyromonas gingivalis, with Toll-Like Receptors-2 and -4 may serve as a risk factor for
the initiation and/or progression of LOAD induced in young wild type mice. However, using the active R01 parent
grant, we recently demonstrated that P. gingivalis-LPS/TLRs axis is attenuated in relation to aging, suggesting
that an alternative pro-inflammatory mechanism may be engaged in the age-dependent pathologies, including
LOAD. Our group also found that P. gingivalis produces a novel class of a host cell-membrane permeable
ceramide lipid termed phosphoglycerol dihydroceramide (PGDHC) which elevates macrophage activation
independently of TLRs. Furthermore, a study demonstrated that among the virulence factors produced by P.
gingivalis, only PGDHC is found abundantly in the periodontal lesions as well as in the blood circulation. In
addition, our preliminary data show that PGDHC is frequentely detected in the postmortem brains of patients
with Alzheimer’s disease compared to that in healthy indviduals. Other preliminary results demonstrated that
PGDHC elevates periodontal inflammation by acting on lysosomal protease Cathepsin B. Furthermore, it was
reported that cathepsin B exacerbated the LOAD-like neuroinflammation and neurodegeneration in a mouse
model of periodontitis induced by P. gingivalis. Although studies of Alzheimer’s disease pathology have
predominantly focused on the amyloid-β and hyperphosphorylated tau, recent multidisciplinary findings strongly
suggest that neuroinflammation associated with aberrant immune responses of the central nervous system
(CNS) resident macrophages, microglia, is the third hallmark features of LOAD. However, it remains elusive
whether PGDHC can promote microglia activation leading to the LOAD neuroinflammation. Based on these lines
of evidence, we hypothesize that, in the context of LOAD-associated neuroinflammation, a novel
PGDHC/Cathepsin B axis is engaged in the microglial activation. In the course of this one-year pilot study, we
will investigate the impact of PGDHC on the cathepsin B-dependent activation of mouse primary microglia cells
in vitro as well as the LOAD-like neuroinflammation and memory skills in relation to aging using female and male
Cathepsin B-knock out and their wild type mice. Then, we will employ the single cell RNA-seq technology to
identify transcriptome profiles between distinct subtypes of microglia isolated from the brains of wild type mice
in relation to aging and sex. The proposed research project will, for the first time, establish the possible role of
P. gingivalis-derived dihydroceramides in neuroinflammation and will provide a fou...

## Key facts

- **NIH application ID:** 10286664
- **Project number:** 3R01AG064003-02S2
- **Recipient organization:** NOVA SOUTHEASTERN UNIVERSITY
- **Principal Investigator:** Alexandru Movila
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $380,000
- **Award type:** 3
- **Project period:** 2019-09-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10286664

## Citation

> US National Institutes of Health, RePORTER application 10286664, Impact of acid ceramidase activity on MIF-mediated migration of circulating osteoclast precursors to periodontal bone lesions in relation to aging (3R01AG064003-02S2). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10286664. Licensed CC0.

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