Restoring mitochondrial quality control through ceramide-induced mitophagy: a potential therapeutic strategy for alzheimer's disease
Active Project Grant Awarded Last action
- Award ID
- F30AG092143
- Recipient
-
The Medical University Of South Carolina UEI NHV3GTWSALA7
- Awarding agency
-
National Institute on Aging
National Institutes of Health, Department of Health and Human Services
- Obligated
- $210,934
Award facts
- Assistance listing
- 93.866 Aging Research
- Completion date 41% complete
- Place of performance
- Charleston, SC 29425, USA
Award details come from USAspending.gov.
Description
- Abstract
- Alzheimer's disease (ad), the primary cause of cognitive decline, is intricately linked to impaired mitophagy, the recycling of damaged mitochondria. This complex pathology may be driven by specific amyloid precursor protein (APP) processing pathways that interfere with mitophagy, which could subsequently promote TAU hyperphosphorylation and amyloid plaque accumulation. Ceramides, bioactive lipids synthesized by ceramide synthase 1 (CERS1), have emerged as crucial regulators in mitophagy and mitochondrial homeostasis. Their role, though pivotal, is not fully delineated. These lipids are known to influence mitophagy through specific signaling pathways, possibly involving receptors such as CERT1, which mediates ceramide transport and distribution, thus affecting mitochondrial health and function. Although ceramides are often criticized for being elevated in ad and associated with negative outcomes, our research proposes a nuanced perspective, suggesting that IT is not the overall abundance but rather a disruption of ceramide homeostasis, specifically decreased ceramides at the mitochondrial membrane, that may be driving the cell's increased ceramide production in an effort to upregulate mitophagy. Regardless, the dysregulation in ceramide levels contributes to neuronal death and ad progression by disrupting these pathways, yet the intricate details of these mechanisms remain to be elucidated. A novel ceramide analog, LCL768, has been synthesized and shows promise in counteracting the detrimental effects of mitochondrial APP accumulation. Preliminary findings suggest that LCL768 may independently modulate ceramide signaling, enhancing the association between mitochondria and autophagosomes and thereby potentially restoring effective mitophagy. The exact molecular action of LCL768 in ad is under investigation, with hypotheses focusing on its interaction with ceramide pathways and mitochondrial membranes, influencing the mitophagic process and neuronal survival. Our research will employ a range of experimental techniques to investigate these mechanisms. Aim 1 will utilize genetic ablation in CERS1 knockout cell and mouse models, alongside molecular assays to assess mitochondrial function and ad progression markers. Imaging techniques, such as fluorescence microscopy, will be used to visualize mitophagy. Aim 2 involves pharmacological intervention with LCL768 in SH-SY5Y neurons and 3XTG ad mice, using behavioral tests to gauge ad symptom alleviation and cellular assays to measure mitophagy enhancement. Expected outcomes from this study include a deeper understanding of ceramide-mediated mitophagy in ad and the potential regulatory role of CERS1. Demonstrating LCL768's efficacy in restoring mitophagy and mitigating ad symptoms could offer a novel therapeutic avenue. The insights gained could impact our understanding of ad pathogenesis, highlighting new targets for intervention and innovative treatments aimed at preserving mitochondrial health and neuronal function, ultimately reducing ad morbidity.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $52,936 | |
| Amendment | $564 | |
| Amendment | $564 | |
| Amendment | $0 | |
| Amendment | $52,290 | |
| Amendment | $52,290 | |
| Original award | $52,290 |
Quick answers
Who received award F30AG092143?
F30AG092143 was awarded to The Medical University Of South Carolina by National Institute on Aging (National Institutes of Health) on July 17, 2025.
How much is award F30AG092143 worth?
$210,934 has been obligated on F30AG092143.
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