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Cell Culturing on 3D Printed LCEs
The purpose of this study is to culture cells on 3D printed structures known as liquid crystal elastomers (LCEs) using templates from microscope scanned tissue specimens. LCEs are composed of a long crosslink of polymers that have a porous property to them that will aid in growth and proliferation of the glial cells once they are seeded into the material. The process by which this is possible is photo curing resin of different types by using multiple formulations of elastomers that contain varying polymerizers. Two main forms of printing are used to accomplish this; an SLA UV curing printer and the use of a custom designed microscope setup. The SLA UV curing printer cures on a layer-by-layer basis at ~30 micron resolution. While the custom designed setup allows for the use of a laser scanning microscope which is capable of providing finer resolution for the LCEs. So far, through the use of the SLA UV curing printer, our lab has been able to print structures of tissue that contain all the characteristics that would make the growth of glial cells a feasible task. The structures were printed using modified materials which contain photo-initiators that enable the material to undergo physical property changes when they react with the UV light from the printer. More specifically, it was a compound by the name of 6arms-alpha (modified), which contains 10% of liquid crystal and has a high viscosity. The importance of this research is to provide a way to study neurons in arrangements that emulate real tissue, which could have a significant impact in the future of bioimplants.Impact of the Methyl Donor Betaine on Repairing Mitochondria in Neurodegenerative Disease
In Alzheimer’s disease (AD) and multiple sclerosis (MS) histone methylation is severely reduced. This hypomethylation leads to aberrant gene expression that brings about disease-causing plaque and lesion buildup within the central nervous system. It is known that this aberrant gene expression affects mitochondria in these diseases. I hypothesized that introducing methyl donors could prevent hypomethylation of histone H3, as well as dysfunction of mitochondria in mouse models of AD and MS. I tested the effects of the methyl donor betaine (also known as trimethylglycine). We administered betaine in drinking water to the APP/PS1 mouse model of AD, and the Cuprizone mouse model of MS for four weeks. The aim of this study was to measure the protective effects of the methyl donor betaine on mitochondrial complexes downregulated in neurodegenerative diseases. Protein was isolated from the brains of mice with and without betaine. The levels of different mitochondrial complex genes in the presence and absence of betaine were measured using Western blotting, JC1 staining, immunohistochemistry (IHC), and densitometry. This research has important implications for developing new therapies to treat AD and MS.- Image
Actigraphy-Based Circadian Measures and Cerebrospinal Fluid Biomarkers of Neurodegeneration in Alzheimer’s Disease with Mild Cognitive Impairment
Although recent data implicates sleep and circadian disruption to neurodegeneration in Alzheimer’s Disease (AD), the association of objective circadian biomarkers and neurodegeneration remains understudied. We hypothesize that actigraphy-based circadian measures are associated with cerebrospinal fluid (CSF) biomarkers of neurodegeneration in those mild cognitive impairment due to AD (MCI-AD).Eighteen patients with CSF biomarker-confirmed MCI-AD underwent actigraphy monitoring generating the following circadian measures: amplitude, F-ratio and mesor and morning collection of CSF biomarkers of neurodegeneration (Aβ42,t-tau,p-tau). Linear models were used to evaluate the association of circadian and CSF measures; logarithmic transformations were performed on neurodegenerative markers for greater normality. Analysis was performed using SAS software. A significance level of 0.05 was assumed for all tests. Eighteen MCI-AD patients who were 68± 6.2 years, 44% female, with median AHI=12 and underwent actigraphy monitoring for 8.2+/-3.2 days were included. There was no significant association of circadian measures and Aβ42 nor with mesor and neurodegeneration biomarkers. Amplitude was associated with both p-tau and t-tau, such that each 10 unit increase in amplitude resulted in a predicted increase in p-tau of 8% (95% CI: 1%-15%, p=0.018) and an increase of 13% (3%-23%; p=0.01) in t-tau. F-ratio was positively associated with p-tau and t-tau; each 1000 unit increase in F-ratio resulted in a predicted 12% (4%-22%; p=0.007) increase in P-tau and 20% (6%-35%; p=0.005) increase in t-tau. Associations of these circadian measures and CSF levels of p-tau and t-tau remained statistically significant after adjustment for age and sex. Among patients with symptomatic MCI stages of AD, objective measures of circadian rhythm disruption are associated with CSF-based biomarkers of neurodegeneration even after consideration of age and sex. - Image
Treating Neuropathology with the Novel Hormone Irisin
Alzheimer’s disease is characterized by neuroinflammation and neural accumulation of pathological tau. One candidate for treatment is a recently discovered hormone irisin, which is a cleaved product from the fibronectin type III domain-containing protein 5 (FNDC5) transmembrane protein. We have preliminary data showing that weekly injections of recombinant irisin decreased neuroinflammation and tau pathology in 4-month old female htau mice that express a mutant, humanized gene associated with late-onset Alzheimer’s disease. In the current study, we determined how changes in treatment frequency and age affected neuropathology, inflammation, and FNDC5 levels in htau mice and their wildtype littermates that lack any form of tau. Impact of Physical Activity on CNS Mitochondrial Metabolism School of Biomedical Sciences, Kent State University Dept. of Biological Sciences, Kent State University Brain Health Research Institute, Kent State University
Multiple sclerosis (MS) is a complex neurodegenerative disease of the central nervous system (CNS) and dysfunctional mitochondria in neurons have been suggested to play a role. Hemoglobin is present in cortical neurons and levels are altered in MS cortex. The role of hemoglobin is unclear, however, hemoglobin β (Hbb) subunit levels are increased in mitochondrial fraction of MS cortex suggesting a potential role of hemoglobin in mitochondrial respiration. In fact, Hbb is tightly bound to chromatin and mediates a signaling mechanism that supports neuronal energetics involving the trimethylation of histone H3 on lysine 4 (H3K4me3), a histone mark that activates transcription of mitochondrial genes and increases mitochondrial respiratory capacity. We are excited by the potential influence that exercise may have on Hbb expression in the CNS and its impact on neuronal energetics. Thus, we compared exercise and sedentary lifestyles on neuronal Hbb expression and mitochondrial metabolism using Sprague Dawley rats. Rats aging 6-8 weeks-old were provided running wheels for a 7 week period. The Hbb expression was shown to be increased in exercised rats compared to sedentary rats. We also observed that increased Hbb expression correlated with an increase in basal neuronal mitochondrial respiration and increased mitochondrial respiration was linked to elevated levels of the neuronal mitochondrial metabolite N-acetylaspartate (NAA). Understanding regulatory mechanisms that impact Hbb expression and how Hbb supports neuronal mitochondria could lead to new therapeutic approaches (including exercise) to treat neurodegenerative diseases including MS, Alzheimer’s, and Parkinson’s where dysfunctional mitochondria contribute to disease activity.