Medicine and Health Sciences Commons^™

Distinct White Matter Changes Associated With Cerebrospinal Fluid Amyloid-Β1-42 And Hypertension, Omar M. Al-Janabi, Christopher A. Brown, Ahmed A. Bahrani, Erin L. Abner, Justin M. Barber, Brian T. Gold, Larry B. Goldstein, Richard R. Murphy, Peter T. Nelson, Nathan F. Johnson, Leslie M. Shaw, Charles D. Smith, John Q. Trojanowski, Donna M. Wilcock, Gregory A. Jicha

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Alzheimer's disease (AD) pathology and hypertension (HTN) are risk factors for development of white matter (WM) alterations and might be independently associated with these alterations in older adults.

OBJECTIVE: To evaluate the independent and synergistic effects of HTN and AD pathology on WM alterations.

METHODS: Clinical measures of cerebrovascular disease risk were collected from 62 participants in University of Kentucky Alzheimer's Disease Center studies who also had cerebrospinal fluid (CSF) sampling and MRI brain scans. CSF Aβ_1-42 levels were measured as a marker of AD, and fluid-attenuated inversion recovery imaging and diffusion tensor imaging were obtained to assess …

Glimepiride Administered In Chow Reversibly Impairs Glucose Tolerance In Mice, Dana M. Niedowicz, Sabire Özcan, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

Sulfonylureas are a class of antidiabetes medications prescribed to millions of individuals worldwide. Rodents have been used extensively to study sulfonylureas in the laboratory. Here, we report the results of studies treating mice with a sulfonylurea (glimepiride) in order to understand how the drug affects glucose homeostasis and tolerance. We tested the effect of glimepiride on fasting blood glucose, glucose tolerance, and insulin secretion, using glimepiride sourced from a local pharmacy. We also examined the effect on glucagon, gluconeogenesis, and insulin sensitivity. Unexpectedly, glimepiride exposure in mice was associated with fasting hyperglycemia, glucose intolerance, and decreased insulin. There was no …

Astrocyte Activation And The Calcineurin/Nfat Pathway In Cerebrovascular Disease, Susan D. Kraner, Christopher M. Norris

Sanders-Brown Center on Aging Faculty Publications

Calcineurin (CN) is a Ca²⁺/calmodulin-dependent protein phosphatase with high abundance in nervous tissue. Though enriched in neurons, CN can become strongly induced in subsets of activated astrocytes under different pathological conditions where it interacts extensively with the nuclear factor of activated T cells (NFATs). Recent work has shown that regions of small vessel damage are associated with the upregulation of a proteolized, highly active form of CN in nearby astrocytes, suggesting a link between the CN/NFAT pathway and chronic cerebrovascular disease. In this Mini Review article, we discuss CN/NFAT signaling properties in the context of vascular disease and …

Isolation Of Cerebral Capillaries From Fresh Human Brain Tissue, Anika M. S. Hartz, Julia A. Schulz, Brent S. Sokola, Stephanie E. Edelmann, Andrew N. Shen, Ralf G. Rempe, Yu Zhong, Nader El Seblani, Bjoern Bauer

Sanders-Brown Center on Aging Faculty Publications

Understanding blood-brain barrier function under physiological and pathophysiological conditions is critical for the development of new therapeutic strategies that hold the promise to enhance brain drug delivery, improve brain protection, and treat brain disorders. However, studying the human blood-brain barrier function is challenging. Thus, there is a critical need for appropriate models. In this regard, brain capillaries isolated from human brain tissue represent a unique tool to study barrier function as close to the human in vivo situation as possible. Here, we describe an optimized protocol to isolate capillaries from human brain tissue at a high yield and with consistent …

Rna Binding Proteins Co-Localize With Small Tau Inclusions In Tauopathy, Brandon F. Maziuk, Daniel J. Apicco, Anna Lourdes Cruz, Lulu Jiang, Peter E. A. Ash, Edroaldo Lummertz De Rocha, Cheng Zhang, Wai Haung Yu, John Leszyk, Jose F. Abisambra, Hu Li, Benjamin Wolozin

Sanders-Brown Center on Aging Faculty Publications

The development of insoluble, intracellular neurofibrillary tangles composed of the microtubule-associated protein tau is a defining feature of tauopathies, including Alzheimer’s disease (AD). Accumulating evidence suggests that tau pathology co-localizes with RNA binding proteins (RBPs) that are known markers for stress granules (SGs). Here we used proteomics to determine how the network of tau binding proteins changes with disease in the rTg4510 mouse, and then followed up with immunohistochemistry to identify RNA binding proteins that co-localize with tau pathology. The tau interactome networks revealed striking disease-related changes in interactions between tau and a multiple RBPs, and biochemical fractionation studies demonstrated …

Ca2+, Astrocyte Activation And Calcineurin/Nfat Signaling In Age-Related Neurodegenerative Diseases, Pradoldej Sompol, Christopher M. Norris

Sanders-Brown Center on Aging Faculty Publications

Mounting evidence supports a fundamental role for Ca²⁺ dysregulation in astrocyte activation. Though the activated astrocyte phenotype is complex, cell-type targeting approaches have revealed a number of detrimental roles of activated astrocytes involving neuroinflammation, release of synaptotoxic factors and loss of glutamate regulation. Work from our lab and others has suggested that the Ca²⁺/calmodulin dependent protein phosphatase, calcineurin (CN), provides a critical link between Ca²⁺ dysregulation and the activated astrocyte phenotype. A proteolyzed, hyperactivated form of CN appears at high levels in activated astrocytes in both human tissue and rodent tissue around regions of amyloid and …

Preventing P-Gp Ubiquitination Lowers Aβ Brain Levels In An Alzheimer's Disease Mouse Model, Anika M. S. Hartz, Yu Zhong, Andrew N. Shen, Erin L. Abner, Björn Bauer

Sanders-Brown Center on Aging Faculty Publications

One characteristic of Alzheimer’s disease (AD) is excessive accumulation of amyloid-β (Aβ) in the brain. Aβ brain accumulation is, in part, due to a reduction in Aβ clearance from the brain across the blood-brain barrier. One key element that contributes to Ab brain clearance is P-glycoprotein (P-gp) that transports Aβ from brain to blood. In AD, P-gp protein expression and transport activity levels are significantly reduced, which impairs Aβ brain clearance. The mechanism responsible for reduced P-gp expression and activity levels is poorly understood. We recently demonstrated that Aβ₄₀ triggers P-gp degradation through the ubiquitin-proteasome pathway. Consistent with these …

Novel Tnf Receptor-1 Inhibitors Identified As Potential Therapeutic Candidates For Traumatic Brain Injury, Rachel K. Rowe, Jordan L. Harrison, Hongtao Zhang, Adam D. Bachstetter, David P. Hesson, Bruce F. O'Hara, Mark I. Greene, Jonathan Lifshitz

Sanders-Brown Center on Aging Faculty Publications

Background: Traumatic brain injury (TBI) begins with the application of mechanical force to the head or brain, which initiates systemic and cellular processes that are hallmarks of the disease. The pathological cascade of secondary injury processes, including inflammation, can exacerbate brain injury-induced morbidities and thus represents a plausible target for pharmaceutical therapies. We have pioneered research on post-traumatic sleep, identifying that injury-induced sleep lasting for 6 h in brain-injured mice coincides with increased cortical levels of inflammatory cytokines, including tumor necrosis factor (TNF). Here, we apply post-traumatic sleep as a physiological bio-indicator of inflammation. We hypothesized the efficacy of novel …

Historical And Cross-Cultural Perspectives On Parkinson's Disease, Lee Xenakis Blonder

Sanders-Brown Center on Aging Faculty Publications

Parkinson’s disease (PD) is a common neurodegenerative disorder, affecting up to 10 million people worldwide according to the Parkinson’s Disease Foundation. Epidemiological and genetic studies show a preponderance of idiopathic cases and a subset linked to genetic polymorphisms of a familial nature. Traditional Chinese medicine and Ayurveda recognized and treated the illness that Western Medicine terms PD millennia ago, and descriptions of Parkinson’s symptomatology by Europeans date back 2000 years to the ancient Greek physician Galen. However, the Western nosological classification now referred to in English as “Parkinson’s disease” and the description of symptoms that define it, are accredited to …

Ketogenic Diet Enhances Neurovascular Function With Altered Gut Microbiome In Young Healthy Mice, David Ma, Amy C. Wang, Ishita Parikh, Stefan J. Green, Jared D. Hoffman, George Chlipala, M. Paul Murphy, Brent S. Sokola, Björn Bauer, Anika M. S. Hartz, Ai-Ling Lin

Sanders-Brown Center on Aging Faculty Publications

Neurovascular integrity, including cerebral blood flow (CBF) and blood-brain barrier (BBB) function, plays a major role in determining cognitive capability. Recent studies suggest that neurovascular integrity could be regulated by the gut microbiome. The purpose of the study was to identify if ketogenic diet (KD) intervention would alter gut microbiome and enhance neurovascular functions, and thus reduce risk for neurodegeneration in young healthy mice (12–14 weeks old). Here we show that with 16 weeks of KD, mice had significant increases in CBF and P-glycoprotein transports on BBB to facilitate clearance of amyloid-beta, a hallmark of Alzheimer’s disease (AD). These neurovascular …

Internal Carotid Artery Stenosis: A Novel Surgical Model For Moyamoya Syndrome, Jill M. Roberts, Michael E. Maniskas, Justin F. Fraser, Gregory J. Bix

Sanders-Brown Center on Aging Faculty Publications

Moyamoya is a cerebrovascular disorder characterized by progressive stenosis of the intracranial internal carotid arteries. There are two forms: Disease and Syndrome, with each characterized by the sub-population it affects. Moyamoya syndrome (MMS) is more prominent in adults in their 20’s-40’s, and is often associated with autoimmune diseases. Currently, there are no surgical models for inducing moyamoya syndrome, so our aim was to develop a new animal model to study this relatively unknown cerebrovascular disease. Here, we demonstrate a new surgical technique termed internal carotid artery stenosis (ICAS), to mimic MMS using micro-coils on the proximal ICA. We tested for …

Disturbance Of Redox Homeostasis In Down Syndrome: Role Of Iron Dysmetabolism, Eugenio Barone, Andrea Arena, Elizabeth Head, D. Allan Butterfield, Marzia Perluigi

Sanders-Brown Center on Aging Faculty Publications

Down syndrome (DS) is the most common genetic form of intellectual disability that leads in the majority of cases to development of early-onset Alzheimer-like dementia (AD). The neuropathology of DS has several common features with AD including alteration of redox homeostasis, mitochondrial deficits, and inflammation among others. Interestingly, some of the genes encoded by chromosome 21 are responsible of increased oxidative stress (OS) conditions that are further exacerbated by decreased antioxidant defense. Previous studies from our groups showed that accumulation of oxidative damage is an early event in DS neurodegeneration and that oxidative modifications of selected proteins affects the integrity …

Down Syndrome, Beta-Amyloid And Neuroimaging, Elizabeth Head, Alex M. Helman, David K. Powell, Frederick A. Schmitt

Sanders-Brown Center on Aging Faculty Publications

This review focuses on the role of Aβ in AD pathogenesis in Down syndrome and current approaches for imaging Aβ in vivo. We will describe how Aβ deposits with age, the posttranslational modifications that can occur, and detection in biofluids. Three unique case studies describing partial trisomy 21 cases without APP triplication, and the occurrences of low level mosaic trisomy 21 in an early onset AD patient are presented. Brain imaging for Aβ includes those by positron emission tomography and ligands (Pittsburgh Compound B, Florbetapir, and FDDNP) that bind Aβ have been published and are summarized here. In combination, we …

Microrna Expression Patterns In Human Anterior Cingulate And Motor Cortex: A Study Of Dementia With Lewy Bodies Cases And Controls, Peter T. Nelson, Wang-Xia Wang, Sarah A. Janse, Katherine L. Thompson

Sanders-Brown Center on Aging Faculty Publications

Overview

MicroRNAs (miRNAs) have been implicated in neurodegenerative diseases including Parkinson’s disease and Alzheimer’s disease (AD). Here, we evaluated the expression of miRNAs in anterior cingulate (AC; Brodmann area [BA] 24) and primary motor (MO; BA 4) cortical tissue from aged human brains in the University of Kentucky AD Center autopsy cohort, with a focus on dementia with Lewy bodies (DLB).

Methods

RNA was isolated from gray matter of brain samples with pathology-defined DLB, AD, AD+DLB, and low-pathology controls, with n=52 cases initially included (n=23 with DLB), all with low (<4hrs) postmortem intervals. RNA was profiled using Exiqon miRNA microarrays. Quantitative PCR for post-hoc replication was performed on separate cases (n=6 controls) and included RNA isolated from gray matter of MO, AC, primary somatosensory (BA 3), and dorsolateral prefrontal (BA 9) cortical regions.

Results

The miRNA expression patterns differed substantially according to …