# Role of glial sphingolipid ceramide in aging and Alzheimer's disease

> **NIH NIH R01** · TEXAS A&M AGRILIFE RESEARCH · 2024 · $536,071

## Abstract

PROJECT SUMMARY
 Aging is the most prominent nongenetic risk factor for age-associated diseases including late onset Alzheimer’s
disease (AD) and related dementias. Accumulating evidence has implicated altered sphingolipid ceramide pathways in
aging and neurodegenerative diseases. However, the cellular and molecular basis underlying ceramide aberration and
how it contributes to aging-associated cognitive decline and AD pathogenesis remains poorly understood. Our
preliminary data revealed aging-dependent accrual of ceramides in astrocytes and, to a less extent, microglia in brain
regions known highly susceptible to aging- and AD-related functional deterioration. Lipidomic analysis of young and
aged mouse brains uncovered specific upregulation of very long chain (VLC) ceramides with concomitant decreases in
corresponding sphingomyelin molecules, suggesting aging-dependent activation of sphingomyelinase. Extracellular
amyloid beta deposition induces robust astroglial and microglial activation and ceramide production in AD as well as in a
mouse model of amyloidosis at even young ages. Moreover, we found significantly elevated acid sphingomyelinase
(aSMase) activity in AD brains compared to age matched controls. Given that elevated astroglial ceramides increase the
vulnerability of oligodendroglia to inflammatory cytokine released by microglia, that oligodendroglia/myelin damage
and/or dysfunction has increasingly implicated in AD pathology, and that ceramides abnormally accumulate in the
microglial lysosomal compartment, we hypothesize that dysregulated ceramide in glial cells is a previously unrecognized
active driver in the progression of aging-related cognitive decline and amyloid pathology. The overarching goal of this
project is to investigate cellular and molecular pathways leading to disruptions of sphingolipid ceramide homeostasis in
physiological aging and amyloidosis conditions and to identify ceramide-mediated pathogenic pathways. Specifically, we
will leverage the powerful sphingolipid targeted lipidomics and cell type-specific genetic manipulation of aSMase and
VLC ceramide synthase CerS2 to (1) determine the effect of VLC ceramide on astrocyte function and paracrine impact on
oligodendroglia and neurons including cellular damage and senescence; (2) investigate the aSMase-ceramide pathway in
regulating microglial clearance of myelin debris and amyloid beta and inflammatory activation; and (3) employ novel
conditional knockout and knockdown mice to determine the contribution of astroglial and microglial aSMase-ceramide
pathway to disease progression in a mouse AD model of amyloidosis. This project shall generate new insights into aging-
related dysregulation of the bioactive ceramide and provide a foundation for exploring the potential of interventions
targeted at sphingolipids and neuroinflammation.

## Key facts

- **NIH application ID:** 10807493
- **Project number:** 1R01AG079320-01A1
- **Recipient organization:** TEXAS A&M AGRILIFE RESEARCH
- **Principal Investigator:** JIANRONG LI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $536,071
- **Award type:** 1
- **Project period:** 2024-01-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10807493

## Citation

> US National Institutes of Health, RePORTER application 10807493, Role of glial sphingolipid ceramide in aging and Alzheimer's disease (1R01AG079320-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10807493. Licensed CC0.

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