Biology subjects

Hartley, M. D.

Publications and source records attributed to Hartley, M. D..

5 recordsLinked to original sources

bioRxiv2026

Quantitative determination of longitudinal CNS cholesterol loss during myelin damage and repair

1.Cholesterol in the central nervous system (CNS) is largely unesterified (>99%) and is predominantly present in the myelin sheath ([~]70% of total CNS cholesterol). Damage to the myelin sheath can result in the conversion of cholesterol to cholesterol esters, which occurs in many neurological diseases, including multiple sclerosis. In this study, we measured longitudinal CNS free cholesterol and cholesterol ester levels in a genetic mouse model during postnatal myelination, demyelination, and remyelination using gas chromatography-mass spectrometry with single ion monitoring technique (GC-MS-SIM) and liquid chromatography mass spectrometry (LC-MS). Cholesterol levels in healthy mouse brains increased up to 38 weeks. In contrast, cholesterol in the healthy spinal cord increased during postnatal timepoints, but then remained steady out to 38 weeks. Interestingly, cholesterol esters in the spinal cord were highest at P1 and drastically reduced by P42, while the brain had similar levels during all postnatal time points. During demyelination, both brain and spinal cord cholesterol levels were significantly reduced as compared to healthy mice and failed to return to normal cholesterol levels even during remyelination. Absolute quantification of cholesterol esters during peak demyelination revealed that cholesterol esters comprise 19% of the total cholesterol pool in the brain and 65% in the spinal cord. The lack of recovery in CNS cholesterol levels after demyelination suggests that healthy de novo cholesterol synthesis pathways are disrupted in this model. Absolute quantification of CNS cholesterol is critical for revealing mechanisms of cholesterol regulation during disease and identifying targets for restoring cholesterol to promote myelin repair.

neuroscience↗

bioRxiv2026

Spinal Cord Microglia Exhibit Impaired Repair Responses to Myelin Damage

BackgroundMultiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that affects both the brain and spinal cord, although the brain has historically received greater attention. In the inducible, oligodendrocyte-specific knockout model of Myrf, which results in white matter damage to both the brain and spinal cord, our laboratory previously demonstrated that the brain undergoes partial remyelination following white matter damage, whereas the spinal cord fails to do so. We also observed that brain microglia display a much stronger activation than spinal cord microglia in this model. Microglia regulate remyelination by clearing myelin debris, processing resulting lipids, and modulating an inflammation response. ResultsHere, to test our hypothesis, we characterized microglial phenotypes during demyelination in both tissues. The brain exhibited greater early microglial recruitment and higher baseline expression of activation and phagocytic markers, suggesting a primed state for responding to damage. In contrast, spinal cord microglia showed delayed phagocytic marker expression, sustained inflammation, and a predominately amoeboid morphology during demyelination. ConclusionsTogether, these findings indicate that brain microglia mount a timely and coordinated response to demyelination that supports remyelination, whereas spinal cord microglia adopt a dysfunctional phenotype that may contribute to impaired myelin repair.

neuroscience↗

bioRxiv2025

Temporal dynamics of CNS cholesterol esters correlate with demyelination and remyelination

Elevated cholesterol ester levels have been observed in the CNS of patients with neurological diseases, yet the source of cholesterol ester accumulation and whether it is directly linked to demyelination remains undefined. This study investigates the temporal dynamics of cholesterol esters using the Plp1-iCKO-Myrf mouse model, which features distinct phases of demyelination and remyelination. Our findings reveal that cholesterol ester levels increased with demyelination in both the brain and the spinal cord. In the brain, cholesterol esters declined to normal levels during remyelination, whereas cholesterol esters remained elevated in the spinal cord, which had limited remyelination. Expression of both acetyl-CoA-acyltransferase 1 (ACAT1) and lecithin-cholesterol acyltransferase (LCAT) were elevated during demyelination, suggesting the potential involvement of both proteins in the formation of cholesterol esters. Co-localization studies revealed that ACAT1 is predominantly expressed by microglia and LCAT is predominantly expressed by astrocytes during demyelination highlighting the active roles of glia cells in cholesterol ester metabolism. In addition, we showed that administering the remyelinating drug, Sob-AM2, effectively reduced the level of cholesterol ester accumulation in the brain during demyelination underscoring the potential that manipulating cholesterol ester regulatory pathways may offer for restoring cholesterol homeostasis and promoting remyelination in demyelinating diseases.

neuroscience↗

bioRxiv2023

Lipidomic analysis reveals differences in the extent of remyelination in the brain and spinal cord

During demyelination, lipid-rich myelin debris is released in the central nervous system (CNS) and must be phagocytosed and processed before new myelin can form. Although myelin comprises over 70% lipids, relatively little is known about how the CNS lipidome changes during demyelination and remyelination. In this study, we obtained a longitudinal lipidomic profile of the brain, spinal cord, and serum using a genetic mouse model of demyelination, known as Plp1-iCKO-Myrf mice. This model has distinct phases of demyelination and remyelination over the course of 24 weeks, in which loss of motor function peaks during demyelination. Using principal component analysis (PCA) and volcano plots, we have demonstrated that the brain and spinal cord have different remyelination capabilities and that this is reflected in different lipidomic profiles over time. We observed that plasmalogens (ether-linked phosphatidylserine and ether-linked phosphatidylcholine) were elevated specifically during the early stages of active demyelination. In addition, we identified lipids in the brain that were altered when mice were treated with a remyelinating drug, which may be CNS biomarkers of remyelination. The results of this study provide new insights into how the lipidome changes in response to demyelination, which will enable future studies to elucidate mechanisms of lipid regulation during demyelination and remyelination.

neuroscience↗

bioRxiv2019

Pharmacological complementation remedies an inborn error of lipid metabolism

X-linked adrenoleukodystrophy (X-ALD) is a rare, genetic disease in which increased very long chain fatty acids (VLCFAs) in the central nervous system (CNS) cause demyelination and axonal degeneration, leading to severe neurological deficits. Sobetirome, a potent thyroid hormone agonist, has been shown to lower VLCFA levels in the periphery and CNS. In this study, two pharmacological strategies for enhancing the effects of thyromimetics were tested in Abcd1 KO mice, a murine model that has the same inborn error in metabolism as X-ALD patients. First, a sobetirome prodrug (Sob-AM2) with increased CNS penetration lowered CNS VLCFAs more potently than sobetirome, and was better tolerated with lower peripheral exposure, but was unable to unable to break the efficacy threshold of CNS VLCFA lowering in Abcd1 KO mice. Second, co-administration of thyroid hormone with sobetirome enhanced VLCFA lowering in the periphery compared to sobetirome alone but did not produce greater lowering in the CNS. These data suggest that the extent of CNS VLCFA lowering in Abcd1 KO mice is limited by a mechanistic threshold related to slow turnover kinetics, potentially related to the lack of frank X-ALD disease in this model. However, Sob-AM2 has improved potency at correcting the lipid abnormality associated with X-ALD in the CNS with better tolerance than the parent drug sobetirome.

pharmacology and toxicology↗