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- All Subjects: Alzheimer's Disease
- Creators: Coleman, Paul
Description
Alzheimer’s disease (AD) is characterized by the degeneration of cholinergic basal forebrain (CBF) neurons in the nucleus basalis of Meynert (nbM), which provides the majority of cholinergic input to the cortical mantle and together form the basocortical cholinergic system. Histone deacetylase (HDAC) dysregulation in the temporal lobe has been associated with neuronal degeneration during AD progression. However, whether HDAC alterations play a role in cortical and cortically-projecting cholinergic nbM neuronal degeneration during AD onset is unknown. In an effort to characterize alterations in the basocortical epigenome semi-quantitative western blotting and immunohistochemistry were utilized to evaluate HDAC and sirtuin (SIRT) levels in individuals that died with a premortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), mild/moderate AD (mAD), or severe AD (sAD). In the frontal cortex, immunoblots revealed significant increases in HDAC1 and HDAC3 in MCI and mAD, followed by a decrease in sAD. Cortical HDAC2 levels remained stable across clinical groups. HDAC4 was significantly increased in prodromal and mild AD compared to aged cognitively normal controls. HDAC6 significantly increased during disease progression, while SIRT1 decreased in MCI, mAD, and sAD compared to controls. Basal forebrain levels of HDAC1, 3, 4, 6 and SIRT1 were stable across disease progression, while HDAC2 levels were significantly decreased in sAD. Quantitative immunohistochemistry was used to identify HDAC2 protein levels in individual cholinergic nbM nuclei immunoreactive for the early phosphorylated tau marker AT8, the late-stage apoptotic tau marker TauC3, and Thioflavin-S, a marker of mature neurofibrillary tangles (NFTs). HDAC2 nuclear immunoreactivity was reduced in individual cholinergic nbM neurons across disease stages, and was exacerbated in tangle-bearing cholinergic nbM neurons. HDAC2 nuclear reactivity correlated with multiple cognitive domains and with NFT formation. These findings identify global HDAC and SIRT alterations in the cortex while HDAC2 dysregulation contributes to cholinergic nbM neuronal dysfunction and NFT pathology during the progression of AD.
ContributorsMahady, Laura Jean (Author) / Mufson, Elliott J (Thesis advisor) / Bimonte-Nelson, Heather A. (Thesis advisor) / Coleman, Paul (Committee member) / Bowser, Robert (Committee member) / Arizona State University (Publisher)
Created2018
Description
The nuclear pore complex is a structure that is found in the nuclear envelope. The nuclear pore complex is made of proteins known as nucleoporins, or Nups. There are many classes of Nups, one of which is Nups with phenylalanine-guanine repeats (FG-Nups). The FG-Nups help control the transport of material through the nuclear pore complex. One type of FG-Nup is NupL2. Previous mRNA data have shown that there is lower expression of NupL2 in Alzheimer's Disease brains than there is in control brains. However, these data are specific to mRNA expression, and do not necessarily extend to NupL2 protein levels. This study focuses on NupL2 levels in non-diseased samples and Alzheimer's Disease samples. Immunohistochemistry (IHC) with 3,3'-diaminobenzidine was performed on temporal neo-cortical brain tissue. Western blots were also performed to quantify the protein levels in non-diseased samples and Alzheimer's Disease samples, and were completed using middle temporal gyrus lysates. The IHC results show that there is more NupL2 protein expression in non-diseased samples than there is in Alzheimer's Disease samples. Likewise, the western blot data show higher NupL2 protein levels in non-diseased samples than in Alzheimer's Disease samples. Both the IHC data and the western blot data indicate that there are higher NupL2 expression levels in non-diseased samples than in Alzheimer's Disease samples. Decreased NupL2 expression in Alzheimer's Disease may indicate that it is not functioning properly. This could lead to the leaking of material between the nucleoplasm and the cytoplasm, which may in turn contribute to Alzheimer's Disease pathogenesis.
ContributorsKulkarni, Neha Uday (Author) / Coleman, Paul (Thesis director) / Mastroeni, Diego (Committee member) / School of Life Sciences (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Alzheimer’s Disease (AD) is the most prevalent form of dementia and is the sixth leading cause of death in the elderly. Evidence suggests that forms of stress, including prenatal maternal stress (PMS), could exacerbate AD development. To better understand the mechanism linking PMS and AD, we investigated behavior and specific epigenetic markers of the 3xTg-AD mouse model compared to aged-controls in offspring of stressed mothers and non-stressed mothers.
ContributorsBrookhouser, Leia (Author) / Coleman, Paul (Thesis director) / Velazquez, Ramon (Committee member) / Conrad, Cheryl (Committee member) / Judd, Jessica (Committee member) / Barrett, The Honors College (Contributor) / Department of Psychology (Contributor)
Created2022-12
Description
Variations in menopause etiologies, from surgical manipulation to a natural transition, can impact cognition in both healthy and neurodegenerative aging. Although abundant research has demonstrated impacts from surgical versus transitional menopause, such as variations in timing of menopause, both variations in initiation of menopause and length of time since menopause, but not all avenues have been systematically evaluated. Further, assessments of variations in hormone therapies have demonstrated marked outcomes on the brain and cognition in different menopause etiologies, and results can differ depending on type of hormone, combination of hormones, dose, route of administration, among other factors, in regard to healthy aging. Further, the impact of the endocrine system on neurodegenerative disease is multifaceted. Research has highlighted that the endocrine system not only impacts neurodegeneration, such as in Alzheimer’s disease (AD), but that fluctuations in the endocrine system might be strong mediators in disease prevalence and progression. This dissertation seeks to understand how factors such as menopause etiology, biological sex, and hormone therapy impact normative and neurodegenerative aging. Assessments in a rat model of normal aging of progestogen-based hormone therapy given during the transition to menopause demonstrated attenuation of impairment seen with transitional menopause that was working memory specific. In evaluating a rat model of AD, there were distinct trends in neuropathology and associated cognitive changes in males and females with and without gonadal hormone deprivation. Further, assessment of transitional menopause in this AD model yielded an interaction between follicular depletion and genotype for neuropathology that was not present in cognitive assessments. Together, these dissertation chapters highlight that there are a multitude of factors to consider when evaluating effects of menopause and that these variations in experience underscore a need for personalized medicine when selecting therapeutic targets for healthy and neurodegenerative aging that includes consideration of overall hormone milieu and menopause history. Further, these data suggest that the inclusion of males and females in the study of AD-related factors is crucial for understanding disease progression.
ContributorsPena, Veronica L (Author) / Bimonte-Nelson, Heather A (Thesis advisor) / Conrad, Cheryl D (Committee member) / Coleman, Paul (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2023
Description
Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder characterized clinically by memory loss, confusion and pathologically by the presence of amyloid beta plaques and neurofibrillary tangles. Even though anti-amyloid vaccination clinical trials have removed amyloid plaques, clinical efficacy has not been achieved during the early phases of AD suggesting that other mechanism play a role in the dementia associated with AD. Mutations in nucleoporin genes have been linked to various human diseases including neurological, nephrotic, cardiac, and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). A recent study found mislocalization of NUP98 and NUP62 in the cytoplasm of human hippocampal neurons in AD (Eftekharzadeh et al., 2019). These NUP’s were associated with phosphorylated-tau, suggesting the depletion of nucleoporins from the nuclear envelope potentially having a direct interaction with phospho-tau. The present study investigated the three differentially expressed NUPs (NUP-214, -93, -153) from different parts of the NPC (cytoplasmic filaments, inner ring structure, nuclear basket) using immunohistochemistry and immunoblotting procedures. This investigation represents one of the first attempts to categorize differential structural changes throughout the NPC in AD.
ContributorsGoras, Miriam (Author) / Coleman, Paul (Thesis director) / Mastroeni, Diego (Committee member) / Mufson, Elliott (Committee member) / Barrett, The Honors College (Contributor) / Microbiology (Contributor)
Created2022-05