Life Sciences Commons^™

Peripheral And Central Glucose Flux In Type I Diabetes, Jelena Anna Juras

Theses and Dissertations--Neuroscience

Diabetes is a complex metabolic disorder, of which high blood glucose concentration is the primary hallmark. Type I diabetes mellitus (T1DM) is characterized by the lack of insulin production, due to a poorly understood autoinflammatory cascade. In the words of historian Barnett “Diabetes may no longer be a death sentence, but for more and more people in the 21st century, it will become a life sentence”, making it the focal point of many research groups. It is estimated that around 20 million individuals worldwide live with T1DM.

Effects of long-term chronically elevated blood glucose are not only seen in micro/macro-vascular …

Insects Provide Unique Systems To Investigate How Early-Life Experience Alters The Brain And Behavior, Rebecca R. Westwick, Clare C. Rittschof

Entomology Faculty Publications

Early-life experiences have strong and long-lasting consequences for behavior in a surprising diversity of animals. Determining which environmental inputs cause behavioral change, how this information becomes neurobiologically encoded, and the functional consequences of these changes remain fundamental puzzles relevant to diverse fields from evolutionary biology to the health sciences. Here we explore how insects provide unique opportunities for comparative study of developmental behavioral plasticity. Insects have sophisticated behavior and cognitive abilities, and they are frequently studied in their natural environments, which provides an ecological and adaptive perspective that is often more limited in lab-based vertebrate models. A range of cues, …

Cortical Iron Disrupts Functional Connectivity Networks Supporting Working Memory Performance In Older Adults, Valentinos Zachariou, Christopher E. Bauer, Elayna R. Seago, Flavius D. Raslau, David K. Powell, Brian T. Gold

Neuroscience Faculty Publications

Excessive brain iron negatively affects working memory and related processes but the impact of cortical iron on task-relevant, cortical brain networks is unknown. We hypothesized that high cortical iron concentration may disrupt functional circuitry within cortical networks supporting working memory performance. Fifty-five healthy older adults completed an N-Back working memory paradigm while functional magnetic resonance imaging (fMRI) was performed. Participants also underwent quantitative susceptibility mapping (QSM) imaging for assessment of non-heme brain iron concentration. Additionally, pseudo continuous arterial spin labeling scans were obtained to control for potential contributions of cerebral blood volume and structural brain images were used to control …

Tonic And Phasic Amperometric Monitoring Of Dopamine Using Microelectrode Arrays In Rat Striatum, Martin Lundblad, David A. Price, Jason J. Burmeister, Jorge E. Quintero, Peter Huettl, Francois Pomerleau, Nancy R. Zahniser, Greg A. Gerhardt

Neuroscience Faculty Publications

Here we report a novel microelectrode array recording approach to measure tonic (resting) and phasic release of dopamine (DA) in DA-rich areas such as the rat striatum and nucleus accumbens. The resulting method is tested in intact central nervous system (CNS) and in animals with extensive loss of the DA pathway using the neurotoxin, 6-hydroxyDA (6-OHDA). The self-referencing amperometric recording method employs Nafion-coated with and without m-phenylenediamine recording sites that through real-time subtraction allow for simultaneous measures of tonic DA levels and transient changes due to depolarization and amphetamine-induced release. The recording method achieves low-level measures of both tonic and …

Amylin As A Potential Link Between Type 2 Diabetes And Alzheimer Disease, Florin Despa, Larry B. Goldstein, Geert Jan Biessels

Pharmacology and Nutritional Sciences Faculty Publications

No abstract provided.

Post-Acquisition Processing Confounds In Brain Volumetric Quantification Of White Matter Hyperintensities, Ahmed A. Bahrani, Omar M. Al-Janabi, Erin L. Abner, Shoshana H. Bardach, Richard J. Kryscio, Donna M. Wilcock, Charles D. Smith, Gregory A. Jicha

Neurology Faculty Publications

BACKGROUND: Disparate research sites using identical or near-identical magnetic resonance imaging (MRI) acquisition techniques often produce results that demonstrate significant variability regarding volumetric quantification of white matter hyperintensities (WMH) in the aging population. The sources of such variability have not previously been fully explored.

NEW METHOD: 3D FLAIR sequences from a group of randomly selected aged subjects were analyzed to identify sources-of-variability in post-acquisition processing that can be problematic when comparing WMH volumetric data across disparate sites. The methods developed focused on standardizing post-acquisition protocol processing methods to develop a protocol with less than 0.5% inter-rater variance.

RESULTS: A series …

Distinct Patterns Of Default Mode And Executive Control Network Circuitry Contribute To Present And Future Executive Function In Older Adults, Christopher A. Brown, Frederick A. Schmitt, Charles D. Smith, Brian T. Gold

Neuroscience Faculty Publications

Executive function (EF) performance in older adults has been linked with functional and structural profiles within the executive control network (ECN) and default mode network (DMN), white matter hyperintensities (WMH) burden and levels of Alzheimer's disease (AD) pathology. Here, we simultaneously explored the unique contributions of these factors to baseline and longitudinal EF performance in older adults. Thirty-two cognitively normal (CN) older adults underwent neuropsychological testing at baseline and annually for three years. Neuroimaging and AD pathology measures were collected at baseline. Separate linear regression models were used to determine which of these variables predicted composite EF scores at baseline …

Macrolide Derivatives Reduce Proinflammatory Macrophage Activation And Macrophage‐Mediated Neurotoxicity, Bei Zhang, Timothy J. Kopper, Xiaodong Liu, Zheng Cui, Steven G. Van Lanen, John C. Gensel

Physiology Faculty Publications

Introduction: Azithromycin (AZM) and other macrolide antibiotics are applied as immunomodulatory treatments for CNS disorders. The immunomodulatory and antibiotic properties of AZM are purportedly independent.

Aims: To improve the efficacy and reduce antibiotic resistance risk of AZM‐based therapies, we evaluated the immunomodulatory and neuroprotective properties of novel AZM derivatives. We semisynthetically prepared derivatives by altering sugar moieties established as important for inhibiting bacterial protein synthesis. Bone marrow‐derived macrophages (BMDMs) were stimulated in vitro with proinflammatory, M1, stimuli (LPS + INF‐gamma) with and without derivative costimulation. Pro‐ and anti‐inflammatory cytokine production, IL‐12 and IL‐10, respectively, was quantified using ELISA. Neuron culture …

Cerebrovascular Smooth Muscle Cells As The Drivers Of Intramural Periarterial Drainage Of The Brain, Roxana Aldea, Roy O. Weller, Donna M. Wilcock, Roxana O Carare, Giles Richardson

Physiology Faculty Publications

The human brain is the organ with the highest metabolic activity but it lacks a traditional lymphatic system responsible for clearing waste products. We have demonstrated that the basement membranes of cerebral capillaries and arteries represent the lymphatic pathways of the brain along which intramural periarterial drainage (IPAD) of soluble metabolites occurs. Failure of IPAD could explain the vascular deposition of the amyloid-beta protein as cerebral amyloid angiopathy (CAA), which is a key pathological feature of Alzheimer's disease. The underlying mechanisms of IPAD, including its motive force, have not been clarified, delaying successful therapies for CAA. Although arterial pulsations from …

Apoe And Alzheimer’S Disease: Neuroimaging Of Metabolic And Cerebrovascular Dysfunction, Jason A. Brandon, Brandon C. Farmer, Holden C. Williams, Lance A. Johnson

Physiology Faculty Publications

Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for late onset Alzheimer’s Disease (AD), and is associated with impairments in cerebral metabolism and cerebrovascular function. A substantial body of literature now points to E4 as a driver of multiple impairments seen in AD, including blunted brain insulin signaling, mismanagement of brain cholesterol and fatty acids, reductions in blood brain barrier (BBB) integrity, and decreased cerebral glucose uptake. Various neuroimaging techniques, in particular positron emission topography (PET) and magnetic resonance imaging (MRI), have been instrumental in characterizing these metabolic and vascular deficits associated with this important AD risk factor. In …

Bilateral Carotid Artery Stenosis Causes Unexpected Early Changes In Brain Extracellular Matrix And Blood-Brain Barrier Integrity In Mice, Jill M. Roberts, Michael E. Maniskas, Gregory J. Bix

Neuroscience Faculty Publications

Bilateral carotid artery stenosis (BCAS) is one experimental model of vascular dementia thought to preferentially impact brain white matter. Indeed, few studies report hippocampal and cortical pathology prior to 30 days post-stenosis; though it is unclear whether those studies examined regions outside the white matter. Since changes in the blood-brain barrier (BBB) permeability precede more overt brain pathology in various diseases, we hypothesized that changes within the BBB and/or BBB-associated extracellular matrix (ECM) could occur earlier after BCAS in the hippocampus, cortex and striatum and be a precursor of longer term pathology. Here, C57Bl/6 mice underwent BCAS or sham surgeries …

Minocycline Protects Developing Brain Against Ethanol-Induced Damage, Xin Wang, Kai Zhang, Fanmuyi Yang, Zhenhua Ren, Mei Xu, Jacqueline A. Frank, Zun-Ji Ke, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Fetal alcohol spectrum disorders (FASD) are caused by ethanol exposure during the pregnancy and is the leading cause of mental retardation. Ethanol exposure during the development results in the loss of neurons in the developing brain, which may underlie many neurobehavioral deficits associated with FASD. It is important to understand the mechanisms underlying ethanol-induced neuronal loss and develop appropriate therapeutic strategies. One of the potential mechanisms involves neuroimmune activation. Using a third trimester equivalent mouse model of ethanol exposure, we demonstrated that ethanol induced a wide-spread neuroapoptosis, microglial activation, and neuroinflammation in C57BL/6 mice. Minocycline is an antibiotic that inhibits …

Highly Conserved Molecular Pathways, Including Wnt Signaling, Promote Functional Recovery From Spinal Cord Injury In Lampreys, Paige E. Herman, Angelos Papatheodorou, Stephanie A. Bryant, Courtney K. M. Waterbury, Joseph R. Herdy, Anthony A. Arcese, Joseph D. Buxbaum, Jeramiah J. Smith, Jennifer R. Morgan, Ona Bloom

Biology Faculty Publications

In mammals, spinal cord injury (SCI) leads to dramatic losses in neurons and synaptic connections, and consequently function. Unlike mammals, lampreys are vertebrates that undergo spontaneous regeneration and achieve functional recovery after SCI. Therefore our goal was to determine the complete transcriptional responses that occur after SCI in lampreys and to identify deeply conserved pathways that promote regeneration. We performed RNA-Seq on lamprey spinal cord and brain throughout the course of functional recovery. We describe complex transcriptional responses in the injured spinal cord, and somewhat surprisingly, also in the brain. Transcriptional responses to SCI in lampreys included transcription factor networks …

Effects Of Environmental Conditions On C-Fos Expression In Rat Nucleus Accumbens After Remifentanil, Usman Z. Hamid, Rebecca S. Hofford, Michael T. Bardo

Oswald Research and Creativity Competition

Previous studies have shown that adolescents raised in impoverished conditions are more likely to develop drug abuse in adulthood. In addition, both stress-inducing living conditions (impoverishment/isolation) and drugs of abuse may lead to an increase in the c-fos transcription factor in the reward circuit of the brain, particularly in the nucleus accumbens. The aim of the current study was to quantify the number of c-fos positive cells in the nucleus accumbens of enriched and isolated rats exposed to the opioid remifentanil. Thirty-two male Sprague-Dawley rats were raised in either enriched or isolated conditions for one month, after which they received …

A Customized Quantitative Pcr Microrna Panel Provides A Technically Robust Context For Studying Neurodegenerative Disease Biomarkers And Indicates A High Correlation Between Cerebrospinal Fluid And Choroid Plexus Microrna Expression, Wang-Xia Wang, David W. Fardo, Gregory A. Jicha, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

MicroRNA (miRNA) expression varies in association with different tissue types and in diseases. Having been found in body fluids including blood and cerebrospinal fluid (CSF), miRNAs constitute potential biomarkers. CSF miRNAs have been proposed as biomarkers for neurodegenerative diseases; however, there is a lack of consensus about the best candidate miRNA biomarkers and there has been variability in results from different research centers, perhaps due to technical factors. Here, we sought to optimize technical parameters for CSF miRNA studies. We examined different RNA isolation methods and performed miRNA expression profiling with TaqMan® miRNA Arrays. More specifically, we developed a customized …

Low Arousal Positive Emotional Stimuli Attenuate Aberrant Working Memory Processing In Persons With Mild Cognitive Impairment, Lucas S. Broster, Shonna L. Jenkins, Sarah D. Holmes, Gregory A. Jicha, Yang Jiang

Behavioral Science Faculty Publications

Emotional enhancement effects on memory have been reported to mitigate the pathophysiology of Alzheimer’s disease (AD). However, relative to their manifestation in persons without pathologic aging, these effects may be reduced in magnitude or even deleterious, especially in tasks that more closely model ecologic memory performance. Based upon a synthesis of such reports, we hypothesized that in persons with AD low arousal positive stimuli would evoke relatively intact emotional enhancement effects, but that high arousal negative stimuli would evoke disordered emotional enhancement effects. To assess this, participants with and without mild cognitive impairment (MCI) presumed to be due to AD …

Chronic Traumatic Encephalopathy-Integration Of Canonical Traumatic Brain Injury Secondary Injury Mechanisms With Tau Pathology, Jacqueline R. Kulbe, Edward D. Hall

Spinal Cord and Brain Injury Research Center Faculty Publications

In recent years, a new neurodegenerative tauopathy labeled Chronic Traumatic Encephalopathy (CTE), has been identified that is believed to be primarily a sequela of repeated mild traumatic brain injury (TBI), often referred to as concussion, that occurs in athletes participating in contact sports (e.g. boxing, football, football, rugby, soccer, ice hockey) or in military combatants, especially after blast-induced injuries. Since the identification of CTE, and its neuropathological finding of deposits of hyperphosphorylated tau protein, mechanistic attention has been on lumping the disorder together with various other non-traumatic neurodegenerative tauopathies. Indeed, brains from suspected CTE cases that have come to autopsy …

Targeting Mitochondrial Dysfunction In Cns Injury Using Methylene Blue; Still A Magic Bullet?, Hemendra J. Vekaria, Lora Talley Watts, Ai-Ling Lin, Patrick G. Sullivan

Spinal Cord and Brain Injury Research Center Faculty Publications

Complex, multi-factorial secondary injury cascades are initiated following traumatic brain injury, which makes this a difficult disease to treat. The secondary injury cascades following the primary mechanical tissue damage, are likely where effective therapeutic interventions may be targeted. One promising therapeutic target following brain injury are mitochondria. Mitochondria are complex organelles found within the cell, which act as powerhouses within all cells by supplying ATP. These organelles are also necessary for calcium cycling, redox signaling and play a major role in the initiation of cell death pathways. When mitochondria become dysfunctional, there is a tendency for the cell to loose …

Clinically Silent Alzheimer's And Vascular Pathologies Influence Brain Networks Supporting Executive Function In Healthy Older Adults, Brian T. Gold, Christopher A. Brown, Jonathan G. Hakun, Leslie M. Shaw, John Q. Trojanowski, Charles D. Smith

Neuroscience Faculty Publications

Aging is associated with declines in executive function. We examined how executive functional brain systems are influenced by clinically silent Alzheimer’s disease (AD) pathology and cerebral white matter hyperintensities (WMHs). Twenty-nine younger adults and thirty-four cognitively normal older adults completed a working memory paradigm while functional magnetic resonance imaging (fMRI) was performed. Older adults further underwent lumbar cerebrospinal fluid (CSF) draw for assessment of AD pathology and FLAIR imaging for assessment of WMHs. Accurate working memory performance in both age groups was associated with high fronto-visual functional connectivity (fC). However, in older adults, higher expression of fronto-visual fC was linked …

Impulsive Personality Dimensions Are Associated With Altered Behavioral Performance And Neural Responses In The Monetary Incentive Delay Task, Ruolei Gu, Yang Jiang, Seth Kiser, Chelsea L. Black, Lucas S. Broster, Yue-Jia Luo, Thomas H. Kelly

Behavioral Science Faculty Publications

Individual differences in dimensions of impulsivity personality including disinhibition and sensation seeking modulate approach responses to reinforcing stimuli, such as drugs and money. The current study examined the effects of monetary incentive on both behavioral performance and electrophysiological activity among individuals varying in disinhibition and sensation seeking. The monetary incentive delay (MID) task was completed under electroencephalogram (EEG) recording. Behavioral data showed that higher disinhibition and sensation-seeking were associated with lower performance accuracy. Event-related potential (ERP) data showed that high reinforcement cues elicited a larger late positive component (LPC) than other conditions among high disinhibition participants, indicating its strong emotional …

Alzheimer's Disease Genetics And Abca7 Splicing, Jared B. Vasquez, James F. Simpson, Ryan Harpole, Steven Estus

Physiology Faculty Publications

Both common and rare polymorphisms within ABCA7 have been associated with Alzheimer’s disease (AD). In particular, the rare AD associated polymorphism rs200538373 was associated with altered ABCA7 exon 41 splicing and an AD risk odds ratio of ∼1.9. To probe the role of this polymorphism in ABCA7 splicing, we used minigene studies and qPCR of human brain RNA. We report aberrant ABCA7 exon 41 splicing in the brain of a carrier of the rs200538373 minor C allele. Moreover, minigene studies show that rs200538373 acts as a robust functional variant in vitro. Lastly, although the ABCA7 isoform with an extended …

Sex Differences In The Drinking Response To Angiotensin Ii (Angii): Effect Of Body Weight, Jessica Santollo, Ann-Marie Torregrossa, Derek Daniels

Biology Faculty Publications

Sex differences in fluid intake stimulated by angiotensin II (AngII) have been reported, but the direction of the differences is inconsistent. To resolve these discrepancies, we measured water intake by male and female rats given AngII. Males drank more than females, but when intake was normalized to body weight, the sex difference was reversed. Weight-matched males and females, however, had no difference in intake. Using a linear mixed model analysis, we found that intake was influenced by weight, sex, and AngII dose. We used linear regression to disentangle these effects further. Comparison of regression coefficients revealed sex and weight differences …

Nfatc2 Modulates Microglial Activation In The Aβpp/Ps1 Mouse Model Of Alzheimer's Disease, Gunjan D. Manocha, Atreyi Ghatak, Kendra L. Puig, Susan D. Kraner, Christopher M. Norris, Colin K. Combs

Pharmacology and Nutritional Sciences Faculty Publications

Alzheimer’s disease (AD) brains are characterized by fibrillar amyloid-β (Aβ) peptide containing plaques and associated reactive microglia. The proinflammatory phenotype of the microglia suggests that they may negatively affect disease course and contribute to behavioral decline. This hypothesis predicts that attenuating microglial activation may provide benefit against disease. Prior work from our laboratory and others has characterized a role for the transcription factor, nuclear factor of activated T cells (NFAT), in regulating microglial phenotype in response to different stimuli, including Aβ peptide. We observed that the NFATc2 isoform was the most highly expressed in murine microglia cultures, and inhibition or …

Peripheral Administration Of The Soluble Tnf Inhibitor Xpro1595 Modifies Brain Immune Cell Profiles, Decreases Beta-Amyloid Plaque Load, And Rescues Impaired Long-Term Potentiation In 5xfad Mice, Kathryn P. Macpherson, Pradoldej Sompol, George T. Kannarkat, Jianjun Chang, Lindsey Sniffen, Mary E. Wildner, Christopher M. Norris, Malú G. Tansey

Sanders-Brown Center on Aging Faculty Publications

Clinical and animal model studies have implicated inflammation and peripheral immune cell responses in the pathophysiology of Alzheimer’s disease (AD). Peripheral immune cells including T cells circulate in the cerebrospinal fluid (CSF) of healthy adults and are found in the brains of AD patients and AD rodent models. Blocking entry of peripheral macrophages into the CNS was reported to increase amyloid burden in an AD mouse model. To assess inflammation in the 5xFAD (Tg) mouse model, we first quantified central and immune cell profiles in the deep cervical lymph nodes and spleen. In the brains of Tg mice, activated (MHCII …

Calcium's Role As Nuanced Modulator Of Cellular Physiology In The Brain, Hilaree N. Frazier, Shaniya Maimaiti, Katie L. Anderson, Lawrence D. Brewer, John C. Gant, Nada M. Porter, Olivier Thibault

Pharmacology and Nutritional Sciences Faculty Publications

Neuroscientists studying normal brain aging, spinal cord injury, Alzheimer’s disease (AD) and other neurodegenerative diseases have focused considerable effort on carefully characterizing intracellular perturbations in calcium dynamics or levels. At the cellular level, calcium is known for controlling life and death and orchestrating most events in between. For many years, intracellular calcium has been recognized as an essential ion associated with nearly all cellular functions from cell growth to degeneration. Often the emphasis is on the negative impact of calcium dysregulation and the typical worse-case-scenario leading inevitably to cell death. However, even high amplitude calcium transients, when executed acutely can …

Translational Models For Vascular Cognitive Impairment: A Review Including Larger Species, Atticus H. Hainsworth, Stuart M. Allan, Johannes Boltze, Catriona Cunningham, Chad Farris, Elizabeth Head, Masafumi Ihara, Jeremy D. Isaacs, Raj N. Kalaria, Saskia A. M. J. Lesnik Oberstein, Mark B. Moss, Björn Nitzsche, Gary A. Rosenberg, Julie W. Rutten, Melita Salkovic-Petrisic, Aron M. Troen

Pharmacology and Nutritional Sciences Faculty Publications

Background: Disease models are useful for prospective studies of pathology, identification of molecular and cellular mechanisms, pre-clinical testing of interventions, and validation of clinical biomarkers. Here, we review animal models relevant to vascular cognitive impairment (VCI). A synopsis of each model was initially presented by expert practitioners. Synopses were refined by the authors, and subsequently by the scientific committee of a recent conference (International Conference on Vascular Dementia 2015). Only peer-reviewed sources were cited.

Methods: We included models that mimic VCI-related brain lesions (white matter hypoperfusion injury, focal ischaemia, cerebral amyloid angiopathy) or reproduce VCI risk factors (old age, hypertension, …

Comparative Proteomic Analyses Of The Parietal Lobe From Rhesus Monkeys Fed A High-Fat/Sugar Diet With And Without Resveratrol Supplementation, Relative To A Healthy Diet: Insights Into The Roles Of Unhealthy Diets And Resveratrol On Function, Aaron M. Swomley, Judy C. Triplett, Jeriel T. Keeney, Govind Warrier, Kevin J. Pearson, Julie A. Mattison, Rafael De Cabo, Jian Cai, Jon B. Klein, D. Allan Butterfield

Chemistry Faculty Publications

A diet consisting of a high intake of saturated fat and refined sugars is characteristic of a Western-diet and has been shown to have a substantial negative effect on human health. Expression proteomics were used to investigate changes to the parietal lobe proteome of rhesus monkeys consuming either a high fat and sugar (HFS) diet, a HFS diet supplemented with resveratrol (HFS+RSV), or a healthy control diet for 2 years. Here we discuss the modifications in the levels of 12 specific proteins involved in various cellular systems including metabolism, neurotransmission, structural integrity, and general cellular signaling following a nutritional intervention. …

Aβ Vaccination In Combination With Behavioral Enrichment In Aged Beagles: Effects On Cognition, Aβ, And Microhemorrhages, Paulina R. Davis, Ginevra Giannini, Karin Rudolph, Nathaniel Calloway, Christopher M. Royer, Tina L. Beckett, M. Paul Murphy, Frederick Bresch, Dieter Pagani, Thomas Platt, Xiaohong Wang, Amy Skinner Donovan, Tiffany L. Sudduth, Wenjie Lou, Erin L. Abner, Richard J. Kryscio, Donna M. Wilcock, Edward G. Barrett, Elizabeth Head

Sanders-Brown Center on Aging Faculty Publications

Beta-amyloid (Aβ) immunotherapy is a promising intervention to slow Alzheimer’s disease (AD). Aging dogs naturally accumulate Aβ and show cognitive decline. An active vaccine against fibrillar Aβ 1–42 (VAC) in aged beagles resulted in maintenance but not improvement of cognition along with reduced brain Aβ. Behavioral enrichment (ENR) led to cognitive benefits but no reduction in Aβ. We hypothesized cognitive outcomes could be improved by combining VAC with ENR in aged dogs. Aged dogs (11–12 years) were placed into 4 groups: (1) control/control (C/C); (2) control/VAC (C/V); (3) ENR/control (E/C); (4) ENR and VAC (E/V) and treated for 20 months. …

Widespread Tau Seeding Activity At Early Braak Stages, Jennifer L. Furman, Jaime Vaquer-Alicea, Charles L. White, Nigel J. Cairns, Peter T. Nelson, Marc I. Diamond

Pathology and Laboratory Medicine Faculty Publications

Transcellular propagation of tau aggregates may underlie the progression of pathology in Alzheimer's disease (AD) and other tauopathies. Braak staging (B1, B2, B3) is based on phospho-tau accumulation within connected brain regions: entorhinal cortex (B1); hippocampus/limbic system (B2); and frontal and parietal lobes (B3). We previously developed a specific and sensitive assay that uses flow cytometry to quantify tissue seeding activity based on fluorescence resonance energy transfer (FRET) in cells that stably express tau reporter proteins. In a tauopathy mouse model, we have detected seeding activity far in advance of histopathological changes. It remains unknown whether individuals with AD also …

Mutation Linked To Autosomal Dominant Nocturnal Frontal Lobe Epilepsy Reduces Low-Sensitivity Α4Β2, And Increases Α5Α4Β2, Nicotinic Receptor Surface Expression, Weston A. Nichols, Brandon J. Henderson, Christopher B. Marotta, Caroline Y. Yu, Chris Richards, Dennis A. Dougherty, Henry A. Lester, Bruce N. Cohen

Chemistry Faculty Publications

A number of mutations in α4β2-containing (α4β2*) nicotinic acetylcholine (ACh) receptors (nAChRs) are linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), including one in the β2 subunit called β2V287L. Two α4β2* subtypes with different subunit stoichiometries and ACh sensitivities co-exist in the brain, a high-sensitivity subtype with (α4)₂(β2)₃ subunit stoichiometry and a low-sensitivity subtype with (α4)₃(β2)₂ stoichiometry. The α5 nicotinic subunit also co-assembles with α4β2 to form a high-sensitivity α5α4β2 nAChR. Previous studies suggest that the β2V287L mutation suppresses low-sensitivity α4β2* nAChR expression in a knock-in mouse model and also that α5 co-expression …