Biology subjects

Williams, H. C.

Publications and source records attributed to Williams, H. C..

3 recordsLinked to original sources

bioRxiv2024

Kir6.2-KATP channels alter glycolytic flux to modulate cortical activity, arousal, and sleep-wake homeostasis

Metabolism plays an important role in the maintenance of vigilance states (e.g. wake, NREM, and REM). Brain lactate fluctuations are a biomarker of sleep. Increased interstitial fluid (ISF) lactate levels are necessary for arousal and wake-associated behaviors, while decreased ISF lactate is required for sleep. ATP-sensitive potassium (KATP) channels couple glucose-lactate metabolism with neuronal excitability. Therefore, we explored how deletion of neuronal KATP channel activity (Kir6.2-/- mice) affected the relationship between glycolytic flux, neuronal activity, and sleep/wake homeostasis. Kir6.2-/- mice shunt glucose towards glycolysis, reduce neurotransmitter synthesis, dampen cortical EEG activity, and decrease arousal. Kir6.2-/- mice spent more time awake at the onset of the light period due to altered ISF lactate dynamics. Together, we show that Kir6.2-KATP channels act as metabolic sensors to gate arousal by maintaining the metabolic stability of each vigilance state and providing the metabolic flexibility to transition between states. HighlightsO_LIGlycolytic flux is necessary for neurotransmitter synthesis. In its absence, neuronal activity is compromised causing changes in arousal and vigilance states despite sufficient energy availability. C_LIO_LIWith Kir6.2-KATP channel deficiency, the ability to both maintain and shift between different vigilance states is compromised due to changes in glucose utilization. C_LIO_LIKir6.2-KATP channels are metabolic sensors under circadian control that gate arousal and sleep/wake transitions. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC="FIGDIR/small/581817v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@11640c6org.highwire.dtl.DTLVardef@1f6a88corg.highwire.dtl.DTLVardef@b38daborg.highwire.dtl.DTLVardef@1a061f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

ApoE4 drives maladaptive heterogeneity and immunometabolic responses of astrocytes

Apolipoprotein E4 (APOE4) is the strongest risk allele associated with the development of late onset Alzheimers disease (AD). Across the CNS, astrocytes are the predominant expressor of APOE while also being critical mediators of neuroinflammation and cerebral metabolism. APOE4 has been consistently linked with dysfunctional inflammation and metabolic processes, yet insights into the molecular constituents driving these responses remain unclear. Utilizing complementary approaches across humanized APOE mice and isogenic human iPSC astrocytes, we demonstrate that ApoE4 alters the astrocyte immunometabolic response to pro-inflammatory stimuli. Our findings show that ApoE4-expressing astrocytes acquire distinct transcriptional repertoires at single-cell and spatially-resolved domains, which are driven in-part by preferential utilization of the cRel transcription factor. Further, inhibiting cRel translocation in ApoE4 astrocytes abrogates inflammatory-induced glycolytic shifts and in tandem mitigates production of multiple pro-inflammatory cytokines. Altogether, our findings elucidate novel cellular underpinnings by which ApoE4 drives maladaptive immunometabolic responses of astrocytes.

neuroscience↗

bioRxiv2022

APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge

The E4 allele of Apolipoprotein E (APOE) is associated with both metabolic dysfunction and a heightened pro-inflammatory response - two findings that may be intrinsically linked through the concept of immunometabolism. Here, we combined bulk, single-cell, and spatial transcriptomics with cell-specific and spatially resolved metabolic analyses to systematically address the role of APOE across age, neuroinflammation, and AD pathology. RNAseq highlighted immunometabolic changes across the APOE4 glial transcriptome, specifically in subsets of metabolically distinct microglia enriched in the E4 brain during aging or following an inflammatory challenge. E4 microglia display increased Hif1 expression, a disrupted TCA cycle, and are inherently pro-glycolytic, while spatial transcriptomics and MALDI mass spectrometry imaging highlight an E4-specific response to amyloid that is characterized by widespread alterations in lipid metabolism. Taken together, our findings emphasize a central role for APOE in regulating microglial immunometabolism.

neuroscience↗