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As a disease-modifying approach for Alzheimer's disease (AD), clioquinol (CQ) targets beta-amyloid (Abeta) reactions with synaptic Zn and Cu yet promotes metal uptake. Here we characterize the second-generation 8-hydroxy quinoline analog PBT2, which also targets metal-induced aggregation of Abeta, but is more effective as a Zn/Cu ionophore and has greater(More)
Previous studies suggest membrane binding is a key determinant of amyloid β (Aβ) neurotoxicity. However, it is unclear whether this interaction is receptor driven. To address this issue, a D-handed enantiomer of Aβ42 (D-Aβ42) was synthesized and its biophysical and neurotoxic properties were compared to the wild-type Aβ42 (L-Aβ42). The results showed D- and(More)
Copper misregulation has been implicated in the pathological processes underlying deterioration of learning and memory in Alzheimer's disease and other neurodegenerative disorders. Supporting this, inhibition of long-term potentiation (LTP) by copper (II) has been well established, but the exact mechanism is poorly characterized. It is thought that an(More)
Increasing evidence has pointed to inhibition of Long Term Potentiation (LTP) by soluble A beta 42 oligomers as central in the etiology of the learning and memory deficits that are hallmarks of Alzheimer Disease. These effects are thought to occur by an interaction between A beta 42 and certain cellular effectors that induce LTP, however, the precise(More)
In the cerebrovascular endothelium, monocarboxylic acid transporter 1 (Mct1) controls blood-brain transport of short chain monocarboxylic and keto acids, including pyruvate and lactate, to support brain energy metabolism. Mct1 function is acutely decreased in rat brain cerebrovascular endothelial cells by β-adrenergic signaling through cyclic adenosine(More)
Monocarboxylic Acid Transporter 1 (MCT1) is expressed on the plasma membrane of cerebrovascular endothelial cells where it is the only known facilitator of lactic acid transport across the blood brain barrier. During stroke, brain injury, and certain other brain pathologies, anaerobic glycolysis produces severe lactic acidosis of brain tissue leading to(More)
Astrocytes exhibit three transmembrane Ca(2+) influx pathways: voltage-gated Ca(2+) channels (VGCCs), the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) class of glutamate receptors, and Na(+)/Ca(2+) exchangers. Each of these pathways is thought to be capable of mediating a significant increase in Ca(2+) concentration ([Ca(2+)](i));(More)
In this study, a detailed characterization of Monocarboxylic Acid Transporter-1 (Mct1) in cytoplasmic vesicles of cultured rat brain microvascular endothelial cells shows them to be a diverse population of endosomes intrinsic to the regulation of the transporter by a brief 25 to 30 minute exposure to the membrane permeant cAMP analog, 8Br-cAMP. The vesicles(More)
21 21 Astrocytes exhibit three transmembrane Ca influx pathways: voltage-gated Ca channels (VGCCs), the a-amino-3-hydroxy-5-1 21 methyl-4-isoxazole propionic acid (AMPA) class of glutamate receptors, and Na / Ca exchangers. Each of these pathways is thought to 21 21 be capable of mediating a significant increase in Ca concentration ([Ca ]); however, the(More)
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