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Epigenetic Dysregulation in the Basocortical Cholinergic Projection System During the Progression of Alzheimer's Disease

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…

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

NupL2 Protein and mRNA Expression is Downregulated in Alzheimer's Disease

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…

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

Prenatal Maternal Stress Alters Alzheimer’s Disease Pathology in 12-Month Old 3xTg Alzheimer’s Disease Mouse Model

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…

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

Implications of Menopause Etiology and Hormonal Alterations in Healthy and Neurodegenerative Aging: Impacts on Learning, Memory, and Neurobiological Outcomes

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,…

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

How Concepts of Electrical Signaling, Neurodegeneration, and Neurogenesis Help Explain the Formation of Higher Cognitive Function from a Geometrical System of Neuronal Microtubules and their Associated Proteins

Description

One very critical aspect of cell biology is the cytoskeleton. The cytoskeleton not only provides a strong foundation for the cell (Pegoraro et al., 2017), but it also allows for protein transport on its tracks that span long distances in cells (Löwe & Amos, 2009), specifically in neurons (Dent, 2017).…

One very critical aspect of cell biology is the cytoskeleton. The cytoskeleton not only provides a strong foundation for the cell (Pegoraro et al., 2017), but it also allows for protein transport on its tracks that span long distances in cells (Löwe & Amos, 2009), specifically in neurons (Dent, 2017). Microtubules have a particular structure as polymers that are part of the cytoskeleton (Dent, 2017). Their components include alpha- and beta-tubulin dimers, and they have dynamic properties, such as polymerization and depolymerization (Dent, 2017). Concerning these dynamic properties and as will be discussed here, specific associated proteins can be useful in electrical signaling, neurodegeneration, and neurogenesis. In this review, I will review relevant findings on microtubule-associated proteins (MAPs), compare these to a prominent drug called taxol, and describe the significance of having a combination of MAPs in the brain. I will suggest that microtubules and their proteins form a critical geometric infrastructure that provides the framework for neuronal structure and function that contributes to more advanced cognitive processes, including consciousness.

ContributorsWilliamson, Elizabeth Paula (Author) / Coleman, Paul (Thesis director) / Mastroeni, Diego (Committee member) / Wolf, George (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)

Created2020-12

Prenatal Maternal Stress Exacerbates Alzheimer’s Disease Through Epigenetic Changes

Description

Stress and stress-related disorders increase the risk of Alzheimer’s Disease (AD) later in life. Some evidence suggests that prenatal maternal stress (PMS) can exacerbate AD. However, the effects of PMS on AD have not been as well studied. Epigenetic changes have been shown to contribute to AD and this is…

Stress and stress-related disorders increase the risk of Alzheimer’s Disease (AD) later in life. Some evidence suggests that prenatal maternal stress (PMS) can exacerbate AD. However, the effects of PMS on AD have not been as well studied. Epigenetic changes have been shown to contribute to AD and this is a possible mechanism by which PMS could accelerate AD. Thus, the present study aimed to investigate the effects of PMS on histone modifications, which change gene expression through alterations made to chromatin structure and thereby DNA accessibility. We utilized female 3xTG-AD mice and performed spatial and learning memory assessments between 5 and 6 months of age. Tissue was analyzed for AD pathology and epigenetic markers at 6 months of age were assessed PMS was shown to influence histone modifications H3K4me3 and H3K27me3 in a manner known to promote the expression of genes associated with neurodegeneration. Further, PMS impaired spatial memory, and, interestingly, the data resembled the pattern of H3K4me3 expression across groups, suggesting that this epigenetic modification could modulate the learning and memory effects of PMS. While the presence of hallmark AD pathologies were not accelerated by PMS, PMS did increase early tau phosphorylation events. Thus, this evidence suggests that PMS impairs spatial memory through epigenetic modifications and may potentially exacerbate AD later in life.

ContributorsCoup, Shelby (Author) / Coleman, Paul (Thesis director) / Velazquez, Ramon (Committee member) / Conrad, Cheryl (Committee member) / Judd, Jessica (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)

Created2022-05

Nuclear Pore Complex Mislocalization in Hippocampal Neurons in Alzheimer’s Disease

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…

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

ANK1 is Up-Regulated in Laser Captured Microglia in Alzheimer’s Brain: The Importance of Addressing Cellular Heterogeneity

Description

Recent epigenetic association studies have identified a new gene, ANK1, in the pathogenesis of Alzheimer’s disease (AD). Although strong associations were observed, brain homogenates were used to generate the data, introducing complications because of the range of cell types analyzed. In order to address the issue of cellular heterogeneity in…

Recent epigenetic association studies have identified a new gene, ANK1, in the pathogenesis of Alzheimer’s disease (AD). Although strong associations were observed, brain homogenates were used to generate the data, introducing complications because of the range of cell types analyzed. In order to address the issue of cellular heterogeneity in homogenate samples we isolated microglial, astrocytes and neurons by laser capture microdissection from CA1 of hippocampus in the same individuals with a clinical and pathological diagnosis of AD and matched control cases. Using this unique RNAseq data set, we show that in the hippocampus, ANK1 is significantly (p<0.0001) up-regulated 4-fold in AD microglia, but not in neurons or astrocytes from the same individuals. These data provide evidence that microglia are the source of ANK1 differential expression previously identified in homogenate samples in AD.

ContributorsMastroeni, Diego (Author) / Sekar, Shobana (Author) / Nolz, Donna (Author) / Delvaux, Elaine (Author) / Lunnon, Katie (Author) / Mill, Jonathan (Author) / Liang, Winnie S. (Author) / Coleman, Paul (Author) / Biodesign Institute (Contributor)

Created2017-07-12