Biology subjects

Snipes, J. A.

Publications and source records attributed to Snipes, J. A..

8 recordsLinked to original sources

bioRxiv2025

Tau pathology reprograms glucose metabolism to support glutamatergic activity and excitatory imbalance

Alzheimers disease (AD) is not only characterized by amyloid-beta (A{beta}) and tau pathology, but also by early and progressive disruptions in metabolism. Neuronal excitability is tightly coupled with metabolic demand, and aberrant excitatory activity - observed in AD patients and models - can drive changes in metabolism. While A{beta}-related metabolic impairments are well-described, less is known about how tau pathology independently contributes to altered metabolic states and excitatory tone. Therefore, we explored how tau pathology impacted whole body and CNS metabolism in mouse models of tauopathy, including the P301S PS19 and Tau4RTg2652 mice. In both models, hyperphosphorylated tau prevents the age-related decline in whole-body metabolism by preserving glucose tolerance and mitigating shifts in fuel utilization (respiratory exchange ratio; RER), suggesting the mice are "glucose needy". Tau pathology also preserves diurnal rhythms in hippocampal interstitial fluid (ISF) glucose and lactate, likely due to increased neuronal activity during the active (dark) phase. Stable isotope-resolved metabolomics following 13C-glucose administration revealed that glucose is preferentially shunted toward glutamate synthesis--at the expense of GABA--highlighting a shift in excitatory/inhibitory balance. Interestingly, these changes were not explained by a primary deficit in synaptic mitochondria but by alterations in glycolytic flux. Adaptations were time of day dependent, where ISF glutamate rises after a glucose injection in the dark period but not the light period. This suggests increased glutamatergic activity may drive metabolic demand during the dark period when mice are more active. Together, these studies fundamentally highlight the important coupling between metabolism and excitability, which is disrupted by hyperphosphorylated tau, tau aggregation, and neurodegeneration. Understanding how tau pathology and metabolism interrelate provides a novel lens for the development of therapeutic targets in late stage AD.

neuroscience↗

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

Novel method for collecting hippocampal interstitial fluid extracellular vesicles (EV-ISF) reveals sex-dependent changes in microglial EV proteome in response to Aβ pathology

Brain-derived extracellular vesicles (EVs) play an active role in Alzheimers disease (AD), relaying important physiological information about their host tissues. Circulating EVs are protected from degradation, making them attractive AD biomarkers. However, it is unclear how circulating EVs relate to EVs isolated from disease-vulnerable brain regions. We developed a novel method for collecting EVs from the hippocampal interstitial fluid (ISF) of live mice. EVs (EVISF) were isolated via ultracentrifugation and characterized by nanoparticle tracking analysis, immunogold labeling, and flow cytometry. Mass spectrometry and proteomic analyses were performed on EVISF cargo. EVISF were 40-150 nm in size and expressed CD63, CD9, and CD81. Using a model of cerebral amyloidosis (e.g. APPswe,PSEN1dE9 mice), we found protein concentration increased but protein diversity decreased with A{beta} deposition. Genotype, age, and A{beta} deposition modulated proteostasis- and immunometabolic-related pathways. Changes in the microglial EVISF proteome were sexually dimorphic and associated with a differential response of plaque associated microglia. We found that female APP/PS1 mice have more amyloid plaques, less plaque associated microglia, and a less robust- and diverse-EVISF microglial proteome. Thus, in vivo microdialysis is a novel technique for collecting EVISF and offers a unique opportunity to explore the role of EVs in AD. Graphical AbstractHippocampal EVISF response to amyloid beta (A{beta}) is sexually dimorphic and related to the microglial EVISF proteome. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/532133v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1a275d6org.highwire.dtl.DTLVardef@e63da5org.highwire.dtl.DTLVardef@1d93cecorg.highwire.dtl.DTLVardef@12ed0db_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Acute hyper- and hypoglycemia uncouples the metabolic cooperation between glucose and lactate to disrupt sleep

The sleep-wake cycle is a master regulator of metabolic and neuronal activity and when altered, can have profound effects on metabolic health and disease. Although consideration is given to how fluctuations in blood glucose affect peripheral physiology and metabolism, less is known about how glucose dysregulation impacts the intrinsic cooperation between brain metabolism and neuronal activity to regulate sleep. To understand the effect of peripheral hyper- and hypoglycemia on these relationships, we paired biosensors measuring hippocampal interstitial fluid (ISF) levels of glucose and lactate with cortical EEG/EMG recordings to produce simultaneous subsecond recordings of ISF glucose, lactate, and sleep-wake states. First, we describe a conserved temporal relationships between ISF glucose and lactate based on their intrinsic oscillations, diurnal rhythms, and sleep/wake cycles. ISF glucose and lactate oscillations are largely anti-correlated but the frequency of their oscillations dictate their power, coherence, and phase. While ISF glucose and lactate both have diurnal fluctuations, only ISF lactate is consistently elevated during wake. During wake, fluctuations in ISF lactate are associated with changes in the EEG power spectrum, suggesting wake-related activity is more closely associated with ISF lactate. Modulation of glucose availability via both hyper- or hypoglycemia disrupts the relationship between peripheral metabolism, brain metabolism, and sleep. Hyper- and hypo-glycemia increase ISF lactate, decrease NREM, and alter EEG spectral activity, again demonstrating ISF lactate drives wake-associated behaviors and disrupts sleep. Taken together, these studies demonstrate that peripheral glucose homeostasis is necessary for maintaining the relationships between brain metabolism, neuronal activity, and sleep-wake patterns and deviations in blood glucose levels are sufficient to disrupt the metabolic signature of sleep-wake states, putting the brain at risk in diseases like type-2-diabetes and Alzheimers disease. Graphical Abstract. Peripheral glucose homeostasis directly modifies sleep/wake patterns O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/507967v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@9102eborg.highwire.dtl.DTLVardef@5699c5org.highwire.dtl.DTLVardef@1897ebeorg.highwire.dtl.DTLVardef@1e00661_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Ethanol exposure alters Alzheimer's-related pathology, behavior, and metabolism

Chronic ethanol exposure can increase amyloid-{beta} (A{beta}) and tau in rodent models of Alzheimers-disease (AD)-like pathology, yet the underlying mechanisms are poorly understood. In this study, a moderate two-bottle choice drinking paradigm was used to identify how chronic ethanol exposure alters A{beta}-related pathology, metabolism, and behavior. Complementary in vivo microdialysis experiments were used to measure how acute ethanol directly modulates A{beta} in the hippocampal interstitial fluid (ISF). Ethanol-exposed APPswe/PSEN1dE9 (APP/PS1) mice showed increased brain atrophy and an increased number of amyloid plaques. Further analysis revealed that ethanol exposure led to a shift in the distribution of plaque size in the cortex and hippocampus. Ethanol-exposed mice developed a greater number of smaller plaques, potentially setting the stage for increased plaque proliferation in later life. Ethanol also induced changes in N-methyl-D-aspartate and {gamma}-aminobutyric acid type-A receptor (NMDAR and GABAAR, respectively) expression, possibly reflecting changes in the excitatory and inhibitory (E/I) balance in the brain. Ethanol exposure also led to a diurnal shift in feeding behavior which was associated with changes in glucose homeostasis and glucose intolerance. Ethanol exposure also exacerbated alterations in the open-field test and deficits in nest-building behaviors in APP/PS1mice. Lastly, an acute dose of ethanol bidirectionally altered hippocampal ISF A{beta} levels - decreasing during the initial exposure and increasing during withdrawal. Acute ethanol exposure increased hippocampal ISF glucose levels, suggesting changes in cerebral glucose metabolism occur in response to ethanol. These experiments indicate that ethanol exacerbates an AD-like phenotype by altering A{beta} deposition, behavior, and metabolism. Here, even a moderate drinking paradigm culminates in an interaction between alcohol use and AD-related phenotypes with a potentiation of AD-related pathology, behavioral dysfunction, and metabolic impairment. HighlightsO_LIChronic ethanol exposure increases brain atrophy in APP/PS1 mice. C_LIO_LIChronic ethanol exposure increased the number of plaques in the brains of APP/PS1 mice. C_LIO_LIChronic ethanol exposure led to dysregulated metabolism in APP/PS1 mice. C_LIO_LIChronic ethanol exposure altered anxiety- and dementia-related behaviors in APP/PS1 mice. C_LIO_LIAcute ethanol exposure bidirectionally alters interstitial fluid (ISF) levels of amyloid-{beta} in APP/PS1 mice during exposure and withdrawal. C_LI

neuroscience↗

bioRxiv2022

Kir6.2-containing KATP channels are necessary for glucose dependent increases in amyloid-beta and Alzheimer's-related pathology

Increased neuronal excitability contributes to amyloid-{beta} (A{beta}) production and aggregation in the Alzheimers disease (AD) brain. Previous work from our lab demonstrated that hyperglycemia, or elevated blood glucose levels, increased brain excitability and A{beta} release potentially through inward rectifying, ATP-sensitive potassium (KATP) channels. KATP channels are present on several different cell types and help to maintain excitatory thresholds throughout the brain. KATP channels are sensitive to changes in the metabolic environment, which are coupled to changes in cellular excitability. Therefore, we hypothesized that neuronal KATP channels are necessary for the hyperglycemic-dependent increases in extracellular A{beta} and eliminating KATP channel activity will uncouple the relationship between metabolism, excitability, and A{beta} pathology. First, we demonstrate that Kir6.2/KCNJ11, the pore forming subunits, and SUR1/ABCC8, the sulfonylurea receptors, are predominantly expressed on excitatory and inhibitory neurons in the human brain and that cortical expression of KCNJ11 and ABCC8 change with AD pathology in humans and rodent models. Next, we crossed APP/PS1 mice with Kir6.2 -/- mice, which lack neuronal KATP channel activity, to define the relationship between KATP channels, A{beta}, and hyperglycemia. Using in vivo microdialysis and hyperglycemic clamps, we explored how acute elevations in peripheral blood glucose levels impacted hippocampal interstitial fluid (ISF) glucose, lactate, and A{beta} levels in APP/PS1 mice with or without KATP channels. Kir6.2+/+, APP/PS1 mice and Kir6.2-/-, APP/PS1 mice were exposed to a high sucrose diet for 6 months to determine the effects of chronic hyperglycemia on A{beta} deposition. We found that elevations in blood glucose levels correlate with increased ISF A{beta}, amyloidogenic processing of amyloid precursor protein (APP), and amyloid plaque pathology in APP/PS mice with intact KATP channels. However, neither acute hyperglycemia nor chronic sucrose overconsumption raised ISF A{beta} or increased A{beta} plaque burden in APP/PS1 mice lacking Kir6.2-KATP channel activity. Mechanistic studies demonstrate ISF glucose not only correlates with ISF A{beta} but also ISF lactate. Without KATP channel activity, ISF lactate does not increase during hyperglycemia, which correlates with decreased monocarboxylate transporter 4 (MCT4) expression, a lactate transporter responsible for astrocytic lactate release. This suggests that KATP channel activity regulates ISF lactate during hyperglycemia, which is important for A{beta} release and aggregation. These studies identify a new role for Kir6.2-KATP channels in Alzheimers disease pathology and suggest that pharmacological antagonism of Kir6.2-KATP channels holds therapeutic promise in reducing A{beta} pathology, especially in diabetic and prediabetic patients.

neuroscience↗

bioRxiv2021

Kidney pathological changes alter cell clustering features in single-cell RNA sequencing

Single cell RNA sequencing (scRNA-Seq) is useful to classify cell-specific gene expression profiles in kidney tissue. As viable cells are required, we report an optimized cell dissociation methodology and the necessity of screening tissue histology prior to scRNA-Seq. We demonstrate that glomerular injury can selectively reduce the appearance of groups of cells during analysis of cell clustering and we confirmed reductions in cell-specific markers among injured cells on kidney sections with fluorescence microscopy. Interpretation of scRNA-Seq results may be refined based upon these considerations.

cell biology↗

bioRxiv2021

Sulfonylureas target the neurovascular response to decrease Alzheimer's pathology

Hyperexcitability is a defining feature of Alzheimers disease (AD), where aberrant neuronal activity is both a cause and consequence of AD. Therefore, identifying novel targets that modulate cellular excitability is an important strategy for treating AD. ATP-sensitive potassium (KATP) channels are metabolic sensors that modulate cellular excitability. Sulfonylureas are KATP channel antagonists traditionally used to combat hyperglycemia in diabetic patients by inhibiting pancreatic KATP channels, thereby stimulating insulin release. However, KATP channels are not limited to the pancreas and systemic modulation of KATP channels has pleotropic physiological effects, including profound effects on vascular function. Here, we demonstrate that human AD patients have higher cortical expression of vascular KATP channels, important modulators of vasoreactivity. We demonstrate that peripheral treatment with the sulfonylurea and KATP channel inhibitor, glyburide, reduced the aggregation and activity-dependent production of amyloid-beta (A{beta}), a hallmark of AD, in mice. Since glyburide does not readily cross the blood brain barrier, our data suggests that glyburide targets vascular KATP channel activity to reduce arterial stiffness, improve vasoreactivity, and normalize pericyte-endothelial cell morphology, offering a novel therapeutic target for AD. Graphical abstractTargeting vascular KATP channel activity for the treatment of Alzheimers disease pathology. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

neuroscience↗