Biology subjects

Popko, B.

Publications and source records attributed to Popko, B..

7 recordsLinked to original sources

bioRxiv2026

Oligodendrocyte stress response as a driver of vascular dementia

Vascular dementia (VaD) is a prevalent and devastating neurocognitive disorder characterized by profound white matter damage, yet the precise cellular mechanisms linking cerebrovascular stress to demyelination remain poorly understood. Here, we characterize the impact of a chronic cardiometabolic stress regimen combining a high-fat diet and hypertension (HF/HBP) on central nervous system structure and function. Adult HF/HBP mice exhibit progressive oligodendroglial cell loss and myelin thinning, followed by cognitive impairments, anxiety-like behavior, and memory deficits that recapitulate clinical features of VaD. Mechanistically, we identify the integrated stress response (ISR) as a central driver of this pathology; pharmacological inhibition of the ISR restores myelination, while cell-specific genetic deletion of the ISR-activating kinase PERK from oligodendrocytes fully protects mice from HF/HBP-induced pathological and behavioral defects. Furthermore, we provide translational evidence that the ISR is activated in oligodendrocytes in human cases of cerebrovascular disease. Together, these findings reveal a critical, cell-autonomous role for oligodendroglial ISR activation during cerebrovascular stress and position this pathway as a viable therapeutic target to mitigate VaD pathogenesis.

neuroscience↗

bioRxiv2025

AA147 Alleviates Symptoms in a Mouse Model of Multiple Sclerosis by Reducing Oligodendrocyte Loss

Inflammation induced oligodendrocyte death and CNS demyelination, are key features of multiple sclerosis (MS). Inflammation-triggered endoplasmic reticulum (ER) stress and oxidative stress promote tissue damage in MS and in its preclinical animal model, experimental autoimmune encephalitis (EAE). Compound AA147 is a potent activator of the ATF6 signaling arm of the unfolded protein response (UPR) that can also induce antioxidant signaling through activation of the NRF2 pathway in neuronal cells. Previous work showed that AA147 protects multiple tissues against ischemia/reperfusion damage through ATF6 and/or NRF2 activation; however, its therapeutic potential in neuroinflammatory disorders remains unexplored. Here, we demonstrate that AA147 ameliorated the clinical symptoms of EAE and reduced ER stress, oligodendrocyte loss, and demyelination. Additionally, AA147 suppressed T cells in the CNS without altering the peripheral immune response. Importantly, AA147 significantly increased the expressions of Grp78, an ATF6 target gene, in oligodendrocytes, while enhancing levels of Grp78 as well as Ho-1, an NRF2 target gene, in microglia. In cultured oligodendrocytes, AA147 promoted nuclear translocation of ATF6, but not NRF2. Intriguingly, AA147 altered the microglia activation profile, possibly by triggering the NRF2 pathway. AA147 was not therapeutically beneficial during the acute EAE stage in mice lacking ATF6 in oligodendrocytes, indicating that protection primarily involves ATF6 activation in these cells. Overall, our results suggest AA147 as a potential therapeutic opportunity for MS by promoting oligodendrocyte survival and regulating microglia status through distinct mechanisms.

neuroscience↗

bioRxiv2022

Myelin lipids as nervous system energy reserves

Neuronal functions and impulse propagation depend on the continuous supply of glucose1,2. Surprisingly, the mammalian brain has no obvious energy stores, except for astroglial glycogen granules3. Oligodendrocytes make myelin for rapid axonal impulse conduction4 and also support axons metabolically with lactate5-7. Here, we show that myelin itself, a lipid-rich membrane compartment, becomes a local energy reserve when glucose is lacking. In the mouse optic nerve, a model white matter tract, oligodendrocytes survive glucose deprivation far better than astrocytes, by utilizing myelin lipids which requires oxygen and fatty acid beta-oxidation. Importantly, fatty acid oxidation also contributes to axonal ATP and basic conductivity. This metabolic support by fatty acids is an oligodendrocyte function, involving mitochondria and myelin-associated peroxisomes, as shown with mice lacking Mfp2. To study reduced glucose availability in vivo without physically starving mice, we deleted the Slc2a1 gene from mature oligodendrocytes. This caused a significant decline of the glucose transporter GLUT1 from the myelin compartment leading to myelin sheath thinning. We suggest a model in which myelin turnover under low glucose conditions can transiently buffer axonal energy metabolism. This model may explain the gradual loss of myelin in a range of neurodegenerative diseases8 with underlying hypometabolism9.

neuroscience↗

bioRxiv2021

Demyelination induces transcriptional reprogramming in proprioceptive and Aβ rapidly adapting low-threshold-mechanoreceptor neurons.

Schwann cells, the main glial cell in the peripheral nervous system (PNS), ensheath bundles of small unmyelinated axons or form myelin on larger axons. PNS injuries initiate transcriptional reprograming in both Schwann cells and sensory neurons that promotes regeneration. While the factors that initiate the transcriptional reprograming in Schwann cells are well characterized, the full range of stimuli that initiate this reprograming in sensory neurons remain elusive. Here, using a genetic model of Schwann cell ablation, we find that Schwann cell loss results in transient PNS demyelination without overt axonal loss. By profiling sensory ganglia at single-cell resolution we show that this demyelination induces transcriptional reprogramming preferably in proprioceptive and A{beta} RA-LTMR neurons. Transcriptional reprograming is assumed to be a cell autonomous response of sensory neurons to mechanical axonal injury. By identifying similar reprograming in non-injured, demyelinated neurons, our study suggests that this reprograming represents a non-cell autonomous transcriptional response of sensory neurons to the loss of axon-Schwann cell interactions. HighlightsO_LIAblation of Schwann cells results in transient PNS demyelination, without overt axonal loss. C_LIO_LISchwann cell loss results in transcriptional reprograming in specific sensory neurons. C_LIO_LISpinal nerve transection (mechanical injury of axons) and demyelination (intact axons) induces similar transcriptional responses in DRG neurons. C_LIO_LIThe transcriptional response to demyelination among DRG neurons is specific to the large myelinated proprioceptive and A{beta} RA-LTMR neurons. C_LI

neuroscience↗

bioRxiv2020

Prolonging the integrated stress response enhances CNS remyelination in an inflammatory environment

The inflammatory environment of demyelinated lesions in multiple sclerosis (MS) patients contributes to remyelination failure. Inflammation activates a cytoprotective pathway, the integrated stress response (ISR), but it remains unclear whether enhancing the ISR can improve remyelination in an inflammatory environment. To examine this possibility, the remyelination stage of experimental autoimmune encephalomyelitis (EAE), as well as a mouse model that incorporates cuprizone-induced demyelination along with CNS delivery of the proinflammatory cytokine IFN-{gamma} were used here. We demonstrate that either genetic or pharmacological ISR enhancement significantly increased the number of remyelinating oligodendrocytes and remyelinated axons in the inflammatory lesions. Moreover, the combined treatment of Sephin1 with the oligodendrocyte differentiation enhancing reagent bazedoxifene increased myelin thickness of remyelinated axons to pre-lesion levels. Taken together, our findings indicate that prolonging the ISR protects remyelinating oligodendrocytes and promotes remyelination in the presence of inflammation, suggesting that ISR enhancement may provide reparative benefit to MS patients.

neuroscience↗

bioRxiv2020

Evaluation of the potassium channel tracer 3F4AP in rhesus macaques

Demyelination causes slowed or failed neuronal conduction and is a driver of disability in multiple sclerosis and other neurological diseases. Currently, the gold standard for imaging demyelination is MRI, but despite its high spatial resolution and sensitivity to demyelinated lesions, it remains challenging to obtain specific and quantitative measures of demyelination. To understand the contribution of demyelination in different diseases and to assess the efficacy of myelin-repair therapies, it is critical to develop new in vivo imaging tools sensitive to changes induced by demyelination. Upon demyelination, axonal K+ channels, normally located underneath the myelin sheath, become exposed and increase in expression, causing impaired conduction. Here, we investigate the properties of the K+ channel PET tracer [18F]3F4AP in primates and its sensitivity to a focal brain injury that occurred three years prior to imaging. [18F]3F4AP exhibited favorable properties for brain imaging including high brain penetration, high metabolic stability, high plasma availability, high reproducibility, high specificity, and fast kinetics. [18F]3F4AP showed preferential binding in areas of low myelin content as well as in the previously injured area. Sensitivity of [18F]3F4AP for the focal brain injury was higher than [18F]FDG, [11C]PiB and [11C]PBR28, and compared favorably to currently used MRI methods.

neuroscience↗

bioRxiv2019

Targeted complement inhibition at synapses prevents microglial synaptic engulfment and synapse loss in demyelinating disease

Multiple sclerosis (MS) is a demyelinating, autoimmune disease of the central nervous system. While work has focused on axon loss in MS, far less is known about synaptic changes. Here, in striking similarity to other neurodegenerative diseases, we identify in postmortem human MS tissue and in nonhuman primate and mouse MS models profound synapse loss and microglial synaptic engulfment. These events can occur independently of local demyelination, neuronal degeneration, and peripheral immune cell infiltration, but coincide with gliosis and increased localization of complement component C3, but not C1q, at synapses. Finally, we use AAV9 to overexpress the complement inhibitor Crry at activated C3-bound synapses in mice and demonstrate robust protection of synapses and visual function. These results mechanistically dissect synapse loss as an early pathology in MS. We further provide a novel gene therapy approach to prevent synapse loss by microglia, which may be broadly applicable to other neurodegenerative diseases.

neuroscience↗