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Case Study

Evaluating the Effect of a Novel Alzheimer’s Disease (AD) Drug

CAD-31 leads to a shift in lipid metabolism, including increases in acylcarnitines, acetyl-CoA, and ketone bodies.

The Metabolon Global Discovery Panel was utilized to establish a CAD-31 metabolomic signature that includes novel biomarkers for treating Alzheimer’s disease. The data from this study demonstrate that in a mouse model of AD, CAD-31 has therapeutic efficacy on the cognitive and physiological parameters of AD. The changes identified in the metabolite profile of CAD-31-treated mice are necessary to determine the physiological consequences of CAD-31 exposure and find markers for target engagement.

The Metabolon Global Discovery Panel was utilized to establish a CAD-31 metabolomic signature that includes novel biomarkers for treating Alzheimer’s Disease. The data from this study demonstrate that in a mouse model of AD, CAD-31 has therapeutic efficacy on the cognitive and physiological parameters of AD. The changes identified in the metabolite profile of CAD-31-treated mice are necessary to determine the physiological consequences of CAD-31 exposure and find markers for target engagement.

Evaluating the Effect of a Novel Alzheimer's Disease (AD) Drug

The Challenge: Understanding the Effect of a Novel Alzheimer’s Disease (AD) Drug

Alzheimer’s disease (AD) is a progressive neurological disorder that causes the brain to atrophy and brain cells to die. AD is the most common cause of dementia, affecting memory, thinking, and behavior. Symptoms of AD eventually become severe enough to interfere with daily tasks. In its early stages, memory loss is mild, but with late-stage AD, individuals lose the capacity to converse, respond to their environment, and function independently. A worldwide effort is underway to find better ways to treat AD, delay its onset, and prevent it from developing. Current therapies may temporarily improve or slow the progression of symptoms; however, no treatment prevents the death of nerve cells in AD. A research group recently synthesized a drug called CAD-31 that was shown to enhance neurogenetic activity in vitro.1 However, to move CAD-31 toward the clinic, further characterization was necessary to demonstrate further the neurogenic, neuroprotective, and memory-enhancing effects of this drug.

Metabolon Insight: Elucidating Potential Biomarkers for CAD-31 Therapy

This study utilized the Metabolon Global Discovery Panel to profile brain (cortex) and plasma samples from drug-treated and vehicle-treated AD and wild-type (WT) mice.1 The goal was to elucidate potential biomarkers for CAD-31 therapy and to further understand the effect that CAD-31 has on metabolism. The Metabolon Global Discovery Panel‘s unrivaled reference dataset of 5,400+ semi-quantifiable analytes offered this group the most comprehensive solution to reveal novel biomarkers of CAD-31 treatment.

The Solution: CAD-31 Leads to a Shift in Lipid Metabolism

The research team studied the effect of CAD-31 in a mouse model of AD at a stage when AD was significantly advanced and examined if CAD-31 could rescue AD-associated deficits. This study demonstrated that when CAD-31 was fed to AD mice for three months, there was a reduction in memory deficit, brain inflammation, and synaptic loss.

Metabolomics data from the brain and plasma of CAD-31-treated and vehicle-treated mice showed that the most prominent effect of CAD-31 is centered on lipid metabolism. The top pathways modified in the plasma of WT mice by CAD-31 were long-chain fatty acids, ketone bodies, acyl carnitines, and sphingolipids. In contrast to the effect of CAD-31 on WT mice, the only significant pathway altered in the plasma of the CAD-31-treated AD group compared with control AD mice was the sphingolipids pathway. The results for brain metabolites of WT mice followed a similar pattern since most changes also occurred in lipid metabolism. In WT mice, long-chain fatty acids and monoacylglycerols were downregulated by CAD-31, whereas acetyl-CoA, acyl carnitines, and ketone bodies were upregulated by CAD-31. The only significant drug effect in AD mice was an increase in monoacylglycerols. Altogether, these metabolic data suggest that CAD-31 leads to a shift in lipid metabolism, reflected by increases in acylcarnitines, acetyl-CoA, and ketone bodies.

The Outcome: Establishing a Metabolomic Signature for CAD-31

The Metabolon Global Discovery Panel was utilized to establish a CAD-31 metabolomic signature that includes novel biomarkers for treating CAD-31. The data from this study demonstrates that in a mouse model of AD, CAD-31 has therapeutic efficacy on the cognitive and physiological parameters of AD. CAD-31 reversed the cognitive deficiencies in AD mice to levels seen in age-matched control animals. The changes identified in the metabolite profile of CAD-31-treated mice are necessary to determine the physiological consequences of CAD-31 exposure and find markers for target engagement.

References

1. Daugherty D, Goldberg J, Fischer W, Dargusch R, Maher P, Schubert D. A novel Alzheimer’s disease drug candidate targeting inflammation and fatty acid metabolism. Alzheimers Res Ther. 2017 Jul 14;9(1):50. doi: 10.1186/s13195-017-0277-3. PMID: 28709449; PMCID: PMC5513091.

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