Browsing by Author "Landreth, Gary"
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Item Air Pollution Exposure and the Lung-Brain Axis: Implications for Alzheimer's Disease(2022-03) Greve, Hendrik Jacob; Oblak, Adrian; Block, Michelle; Nass, Richard; Landreth, GaryAlzheimer’s disease (AD) is a devastating neurodegenerative disease that is expected to affect approximately 6.2 million Americans. Despite its high prevalence, the mechanisms underlying AD remain poorly understood. In recent years, increasing reports indicate that exposure to urban air pollution is a risk factor for the development of AD. However, the mechanistic underpinnings of this association are not well studied. Rats exposed to diesel exhaust (DE) showed neuroinflammation and impaired expression of TREM2 and disease-associated microglia (DAM), a cell subtype hypothesized to play beneficial roles during neurodegeneration, markers. Microglia in the cortex of rats exposed to DE, also showed decreased association with the vasculature, providing a novel link between the microglia and the brain vasculature. Examining the functional role of TREM2 during DE exposures, Trem2-/- mice showed an altered pro-inflammatory profile in both the brain and lungs in response to DE particles as well as altered phagocytic oxidase related gene expression. Examining another prominent component of air pollution, ozone (O3), in a mouse model of AD, it was discovered that subchronic O3 exposure exacerbates amyloid pathology through impaired microglial-plaque association in 5xFAD mice. 5xFAD mice exposed to O3 also showed increased expression of pro-inflammatory cytokines, increased markers of dystrophic neurites, and decreased expression of key acetylcholinergic pathway components. Examining the peri-plaque microenvironment, it was discovered that O3 dysregulates key DAM proteins and amyloid processing proteins. In the lung, it was found that O3 exacerbated immune cell infiltration in 5xFAD mice compared to WT controls, suggesting that ongoing amyloid pathology regulates pulmonary immune response to air pollution. To examine how O3-induced pulmonary immune responses may be signaling to the CNS, we examined the serum of 5xFAD mice, where HMGB1, VEGF, and IL-9 were upregulated. Injection of rHMGB1 into mice showed similar gene changes to 5xFAD mice exposed to O3, along with impaired Trem2 expression. Using a peripheral myeloid specific knock-out model of HMGB1, we also show that HMGB1 regulates O3-induced Trem2 expression impairment. Taken together, these data support that air pollution exposure impairs TREM2, DAM cells, and the microglial plaque response through a bidirectional lung-brain axis to exacerbate AD-like pathology.Item APOE4 Drives Impairment in Astrocyte-Neuron Coupling in Alzheimer's Disease and Works Through Mechanisms in Early Disease to Influence Pathology(2023-05) Brink, Danika Marie Tumbleson; Lamb, Bruce; Bissel, Stephanie; Herbert, Brittney-Shea; Landreth, Gary; Puntambekar, Shweta; Saykin, Andrew; Zhang, ChiAlzheimer’s disease (AD) is a neurodegenerative disorder resulting in progressive memory loss, brain atrophy, and eventual death. AD pathology is characterized by the accumulation of neurotoxic amyloid-beta (Aβ) plaques, synapse loss, neurofibrillary tangles (NFTs), and neurodegeneration. The APOE4 allele is associated with a 3-fold increased risk for AD and results in increased Aβ plaque deposition, reduced Aβ clearance, and reduced synaptic plasticity. Although APOE expression is upregulated in microglia in AD, APOE is expressed primarily by astrocytes in the CNS. It is not well understood how astrocytic APOE drives the mechanisms that result in worsened AD outcomes. Here, digital spatial profiling and bioinformatics data suggest that APOE4 causes transcriptional dysregulation in early AD and may disrupt neuronal processes via astrocytes. Whole transcriptome data from plaque and non-plaque regions in the cortices and hippocampus of 4- and 8-month-old AD model mice expressing humanized APOE4/4 or APOE3/3 (control) were analyzed. Transcriptional dysregulation was increased in APOE4/4 AD mice compared to that in APOE3/3 at 4 but not 8 months of age, suggesting that early dysregulation of APOE4-driven disease mechanisms may shape degenerative outcomes in late-stage AD. Additionally, APOE4/4 potentially functions via plaque-independent mechanisms to influence neuronal function in early AD before the onset of pathology. Single-nuclei RNA sequencing data were obtained from human post-mortem astrocytes and the bioinformatic analyses revealed a novel astrocyte subtype that highly expresses several top genes involved in functional alterations associated with APOE4, including neuronal generation, development, and differentiation, and synaptic transmission and organization. Overall, our findings indicate that APOE4 may drive degenerative outcomes through the presented astrocyte candidate pathways. These pathways represent potential targets for investigations into early intervention strategies for APOE4/4 patients.Item Cellular and Molecular Targets in the Neuroendocrine System That Defend Against Diabetes, Obesity, and Alzheimer's Disease(2021-09) Reilly, Austin Michael; Sheets, Patrick; Ren, Hongxia; Baucum, Anthony II; Evans-Molina, Carmella; Landreth, GaryMetabolic survival mechanisms that defend body weight and conserve energy are currently at odds with modernized society which has a food supply that is ubiquitous, calorie dense, and highly palatable. Chronic overnutrition leads to a metabolic syndrome of obesity, insulin resistance, inflammation, and cardiovascular diseases that is increasingly prevalent and threatens health on a global scale. The brain is both a victim and culprit of metabolic diseases, and prolonged metabolic dysfunction can exacerbate the pathological mechanisms underlying both metabolic and neurodegenerative diseases. Since neuroendocrine pathways comprise an essential feedback mechanism that detects circulating hormones and nutrients in order to regulate satiety, energy expenditure, and glucose homeostasis, our research goals were to characterize molecular mechanisms within neuroendocrine pathways that could be leveraged for treating obesity, diabetes, and Alzheimer’s disease. First, we identified the expression of a G protein-coupled receptor, Gpr17, in POMC neurons and discovered that it protects aged mice from high-fat diet (HFD)-induced metabolic derangements. We examined the electrophysiological properties of POMC neurons and found Gpr17 deficiency led to increased spontaneous action potentials. Moreover, Pomc-Cre-driven Gpr17 knockout (PGKO) mice, especially female knockouts, had increased POMC-derived alpha-melanocyte stimulating hormone and beta-endorphin despite a comparable level of prohormone POMC in their hypothalamic extracts. Second, we generated a highly insulin resistant mouse model with human GLUT4 promoter-driven insulin receptor knockout (GIRKO) in muscle, adipose, and GLUT4-expressing neuronal subpopulations. This genetic approach recapitulates the primary defect preceding type 2 diabetes (T2D) and revealed additional factors/mechanisms that drive the ultimate progression of overt diabetes. Third, we used 5xFAD mice as a model of Alzheimer’s disease and showed that they were more susceptible to HFD-induced metabolic dysregulation and expression of AD pathological markers in the hippocampus. Our results helped elucidate the molecular and cellular mechanisms responsible for increased AD pathology in high-fat diet-fed 5xFAD mice and suggest that metabolic dysfunctions are a therapeutic target to ameliorate AD pathology. In conclusion, metabolic diseases are pervasive and require nuanced approaches that target the neuroendocrine system in order to restore metabolic homeostasis and protect the brain from neurodegenerative processes that are associated with obesity and diabetes.Item Cholesterol-Metabolizing Enzyme Cytochrome P450 46A1 as a Pharmacologic Target for Alzheimer’s Disease(Elsevier, 2017-09) Mast, Natalia; Saadane, Aicha; Valencia-Olvera, Ana; Constans, James; Maxfield, Erin; Arajawa, Hiroyuki; Li, Young; Landreth, Gary; Pikuleva, Irina A.; Department of Anatomy & Cell Biology, IU School of MedicineCytochrome P450 46A1 (CYP46A1 or cholesterol 24-hydroxylase) controls cholesterol elimination from the brain and plays a role in higher order brain functions. Genetically enhanced CYP46A1 expression in mouse models of Alzheimer's disease mitigates the manifestations of this disease. We enhanced CYP46A1 activity pharmacologically by treating 5XFAD mice, a model of rapid amyloidogenesis, with a low dose of the anti-HIV medication efavirenz. Efavirenz was administered from 1 to 9 months of age, and mice were evaluated at specific time points. At one month of age, cholesterol homeostasis was already disturbed in the brain of 5XFAD mice. Nevertheless, efavirenz activated CYP46A1 and mouse cerebral cholesterol turnover during the first four months of administration. This treatment time also reduced amyloid burden and microglia activation in the cortex and subiculum of 5XFAD mice as well as protein levels of amyloid precursor protein and the expression of several genes involved in inflammatory response. However, mouse short-term memory and long-term spatial memory were impaired, whereas learning in the context-dependent fear test was improved. Additional four months of drug administration (a total of eight months of treatment) improved long-term spatial memory in the treated as compared to the untreated mice, further decreased amyloid-β content in 5XFAD brain, and also decreased the mortality rate among male mice. We propose a mechanistic model unifying the observed efavirenz effects. We suggest that CYP46A1 activation by efavirenz could be a new anti-Alzheimer's disease treatment and a tool to study and identify normal and pathological brain processes affected by cholesterol maintenance.Item Elucidating the Influence of Microglia on Retinal Ganglion Cells in a Human Pluripotent Stem Cell Model(2024-06) Harkin, Jade; Meyer, Jason; Sheets, Patrick; Landreth, Gary; Block, Michelle; Sharma, Tasneem; Gomes, CatiaGlaucoma is a complex disease that leads to irreversible blindness, characterized by the loss of retinal ganglion cells (RGCs), which are the cells that transmit visual information from your eye into your brain. Evidence suggests that microglia, the resident immune cells in the central nervous system, may have a detrimental role in the onset and the progression of glaucoma. Microglia become activated in response to damage, pathogens and toxins and are initially thought to be beneficial to RGCs. However, when these cells are activated for excessive periods of time, they are thought to be harmful to RGCs. Thus, we sought to develop novel human pluripotent stem cell (hPSC)-derived microglia, astrocyte and RGC co-cultures to determine how microglia activation modulates RGC phenotypes in a human cellular model. Healthy and LPS-activated microglia were first co-cultured with RGCs for up to 3 weeks and the effects of microglia upon RGCs were assessed. Additionally, healthy and LPS-activated microglia were also co-cultured with astrocytes and RGCs for up to three weeks to assess if LPS-treated microglia can activate astrocytes and the effects this would have on RGCs. Results showed that when co-cultured with RGCs alone for 1 week, microglia activation is initially beneficial to RGCs. However, when co-cultured with RGCs for 3 weeks, microglia activation leads to RGC damage. Consequently, when astrocytes are present, microglia activation is harmful to RGCs in both short-term and long-term co-cultures, suggesting an additional role for microglia modulation of astrocytes, further leading to neurodegeneration. Taken together, our results have allowed for the precise study of how individual cell types are adversely affected in disease-relevant states, how microglia can directly influence RGCs, and how multiple co-cultures of human microglia, astrocytes and RGCs allows for a more sophisticated investigation of cellular interactions in disease states relevant to glaucoma.Item Multisystem Effects of Mold Inhalation: A Convergence on the Central Nervous System(2020-08) Ladd, Thatcher Bondi; Oblak, Adrian L.; Yoder, Karmen K.; Baucum, Anthony J. II; Truitt, William; Landreth, GaryWith urbanization, indoor exposure to microbial communities has changed significantly. While indoor bacterial exposure has decreased, indoor fungal exposure has increased. Along with increases in fungal species diversity, indoor air in urbanized countries is characterized by 1,000+ fold differences in mold spore density between buildings. Americans are estimated to spend ~87% of their lives in this new indoor environment, where airborne spore concentrations are unregulated. While the effects of mold exposure on certain respiratory diseases are well established, little is known about how inhaled mold affects extra-respiratory disease. Mold exposure is associated with central nervous system (CNS) symptoms in humans, but very little is known about how mold affects the CNS. Here, I show that subchronic inhalation of a common indoor mold, Aspergillus versicolor, causes neuroinflammatory gene transcription in five out of five brain regions tested, at both 1 and 2 days post inhalation. How peripheral inflammation from mold inhalation causes neuroinflammation is unknown. The mechanisms by which mold is inhaled and cleared implicate the lung, systemic circulation, and gastrointestinal tract as potential areas of immune response. After mold spores are inhaled and deposited in the lung, they are killed by antifungal immunity, cleared from the lung by the mucociliary escalator, swallowed, and excreted through the gastrointestinal tract. Molds produce many mycotoxins which enter enterohepatic recirculation with known toxic effects, including intestinal epithelial disruption. Mycotoxin concentrations in food are regulated in countries comprising ~85% of the world’s population. Inhaled molds produce these same mycotoxins, yet pulmonary exposure is unregulated. The multi-system effects of fungal exposure are poorly understood, and are part of a growing nascent field. Here, I discuss the current state of the indoor fungal environment, known health effects of mold exposure, how fungi activate the immune system, the CNS effects of a common indoor mold, how neuroinflammation from mold exposure might be occurring, future work needed for the systematic analysis of the CNS effects of mold, what is needed to determine the extent to which fungal exposure influences disease, and what might be done to mitigate those effects.Item The Neuroinflammatory Response Associated to Cerebral Amyloid Angiopathy (CAA)(2021-12) Taylor, Xavier Nathaniel; Kim, Jungsu; Landreth, Gary; Oblak, Adrian; Vidal, Ruben; Lasagna-Reeves, CristianCerebral amyloid angiopathy (CAA) is characterized by the cerebrovascular deposition of amyloid. The mechanisms underlying the contribution of CAA to neurodegeneration are not fully understood. In this dissertation, there are three main chapters. The first chapter investigates existing evidence regarding the amyloid diversity in CAA and its relation to tau pathology and immune response, as well as the possible contribution of molecular and cellular mechanisms, previously associated with parenchymal amyloid in Alzheimer disease (AD) and AD-related dementias, to the pathogenesis of CAA. The second chapter demonstrates differential glial reactivity and activation associated with early-stage CAA in a mouse model of Familial Danish Dementia (FDD), a neurodegenerative disease characterized by vascular accumulation of Danish amyloid (ADan). We show that early-stage CAA is associated with dysregulation in immune response networks and lipid processing, severe astrogliosis with a neurotoxic A1-astrocytic phenotype, characterized by increased expression of Complement Component 3 (C3), and decreased levels of Triggering Receptor Expressed On Myeloid Cells 2 (Trem2) with no significant reactive microgliosis. Our results also indicate how cholesterol accumulation and Apolipoprotein E (ApoE) are associated with vascular amyloid deposits at the early stages of pathology. Furthermore, we demonstrate A1 astrocytic mediation of Trem2 and microglia homeostasis. In the final chapter, we addressed whether inflammatory stimulus of other cell types are capable of inducing a subtype of neurotoxic astrocytes. Here we show a subtype of C3+ neurotoxic astrocyte are induced by activated endothelial cells that is distinct from astrocytes classically activated by microglia. We show that endothelial activated astrocytes have upregulated expression of A1-astrocytic genes and exhibit a distinctive extracellular matrix remodeling profile. Finally, we demonstrate that endothelial activated astrocytes are Decorin-positive and are associated to vascular amyloid deposits but not parenchymal amyloid plaques in mouse models and AD/CAA patients. These findings show the existence of potentially extensive and subtle functional diversity of C3+-reactive astrocytes.Item PPARβ/δ-agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes(Wiley, 2018-11-19) Konttinen, Henna; Gureviciene, Irina; Oksanen, Minna; Grubman, Alexandra; Loppi, Sanna; Huuskonen, Mikko T.; Korhonen, Paula; Lampinen, Riikka; Keuters, Meike; Belaya, Irina; Tanila, Heikki; Kanninen, Katja M.; Goldsteins, Gundars; Landreth, Gary; Koistinaho, Jari; Malm, Tarja; Anatomy and Cell Biology, School of MedicineAstrocytes are the gatekeepers of neuronal energy supply. In neurodegenerative diseases, bio-energetics demand increases and becomes reliant upon fatty acid oxidation as a source of energy. Defective fatty acid oxidation and mitochondrial dysfunctions correlate with hippocampal neurodegeneration and memory deficits in Alzheimer’s disease (AD), but it is unclear whether energy metabolism can be targeted to prevent or treat the disease. Here we show for the first time an impairment in fatty acid oxidation in human astrocytes derived from induced pluripotent stem cells of AD patients. The impairment was corrected by treatment with a synthetic peroxisome proliferator activated receptor delta (PPARβ/δ) agonist GW0742 which acts to regulate an array of genes governing cellular metabolism. GW0742 enhanced the expression of CPT1a, the gene encoding for a rate-limiting enzyme of fatty acid oxidation. Similarly, treatment of a mouse model of AD, the APP/PS1-mice, with GW0742 increased the expression of Cpt1a and concomitantly reversed memory deficits in a fear conditioning test. Although the GW0742-treated mice did not show altered astrocytic glial fibrillary acidic protein-immunoreactivity or reduction in amyloid beta (Aβ) load, GW0742 treatment increased hippo-campal neurogenesis and enhanced neuronal differentiation of neuronal progenitor cells. Furthermore, GW0742 prevented Aβ-induced impairment of long-term potentiation in hippocampal slices. Collectively, these data suggest that PPARβ/δ-agonism alleviates AD related deficits through increasing fatty acid oxidation in astrocytes and improves cognition in a transgenic mouse model of AD.Item Training Physician-Scientists in Social and Behavioral Science: Indiana ADRD Medical Scientist Training Program(Oxford University Press, 2022-12-20) Fowler, Nicole; Herbert, Brittney-Shea; Callahan, Christopher; Peng, Siyun; Perry, Brea; Yoder, Karmen; Landreth, Gary; Truitt, William; Medicine, School of MedicineThere is a critical need to grow and strengthen the pipeline of physician scientists who have expertise in sociomedical and behavioral research and are dedicated to addressing the nation's challenges posed by Alzheimer's disease and related dementias (ADRD). In 2021 The Indiana ADRD Medical Scientist Training Program (IADRD MSTP) was designed to meet this need and is built on the infrastructure of a robust portfolio of ADRD research, graduate training programs in medical neurosciences and sociology, and our existing MD-PhD program at Indiana University School of Medicine. The Aims of the IADRD MSTP are: 1) To recruit and train a competitive pool of diverse students who have an interest and commitment to social and behavioral research and patient care focused on ADRD; 2) To engage MD-PhD students early in mentored sociomedical and behavioral research that integrates IUs systems-based medical training curriculum with our cutting edge ADRD research that reinforces commitment and minimizes attrition of physician-scientists ADRD; and 3) To graduate students with dual MD-PhD degrees with strong methodological training in social and behavioral science and experts in ADRD who will be successful independent investigators at the best academic medical centers nationwide. The program includes rigorous didactic training in social, behavioral, and clinical research methods, with flexibility to allow students to focus their effort on one methodological area of interest; early initiation of ADRD research experiences with multidisciplinary teams of mentors and advisors; and the provision of educational experiences that enhance students' abilities to become independent researchers.