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Nicol, N. I.

Publications and source records attributed to Nicol, N. I..

2 recordsLinked to original sources
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↗