Cellular Senescence Is Induced by the Environmental Neurotoxin Paraquat and Contributes to Neuropathology Linked to Parkinson’s Disease

Exposure to the herbicide paraquat (PQ) is associated with an increased risk of idiopathic Parkinson’s disease (PD). Therapies based on PQ’s presumed mechanisms of action have not, however, yielded effective disease therapies. Cellular senescence is an anticancer mechanism that arrests proliferation of replication-competent cells and results in a pro-inflammatory senescence-associated secretory phenotype (SASP) capable of damaging neighboring tissues. Here, we demonstrate that senescent cell markers are preferentially present within astrocytes in PD brain tissues. Additionally, PQ was found to induce astrocytic senescence and an SASP in vitro and in vivo, and senescent cell depletion in the latter protects against PQ-induced neuropathology. Our data suggest that exposure to certain environmental toxins promotes accumulation of senescent cells in the aging brain, which can contribute to dopaminergic neurodegeneration. Therapies that target senescent cells may constitute a strategy for treatment of sporadic PD, for which environmental exposure is a major risk factor

Cellular Senescence Is Induced by the Environmental Neurotoxin Paraquat and Contributes to Neuropathology Linked to Parkinson's Disease

Exposure to the herbicide paraquat (PQ) is associated with an increased risk of idiopathic Parkinson’s disease (PD). Therapies based on PQ’s presumed mechanisms of action have not, however, yielded effective disease therapies. Cellular senescence is an anticancer mechanism that arrests proliferation of replication-competent cells and results in a pro-inflammatory senescence-associated secretory phenotype (SASP) capable of damaging neighboring tissues. Here, we demonstrate that senescent cell markers are preferentially present within astrocytes in PD brain tissues. Additionally, PQ was found to induce astrocytic senescence and an SASP in vitro and in vivo, and senescent cell depletion in the latter protects against PQ-induced neuropathology. Our data suggest that exposure to certain environmental toxins promotes accumulation of senescent cells in the aging brain, which can contribute to dopaminergic neurodegeneration. Therapies that target senescent cells may constitute a strategy for treatment of sporadic PD, for which environmental exposure is a major risk factor

Absence of microglia promotes diverse pathologies and early lethality in Alzheimer’s disease mice

Microglia are strongly implicated in the development and progression of Alzheimer's disease (AD), yet their impact on pathology and lifespan remains unclear. Here we utilize a CSF1R hypomorphic mouse to generate a model of AD that genetically lacks microglia. The resulting microglial-deficient mice exhibit a profound shift from parenchymal amyloid plaques to cerebral amyloid angiopathy (CAA), which is accompanied by numerous transcriptional changes, greatly increased brain calcification and hemorrhages, and premature lethality. Remarkably, a single injection of wild-type microglia into adult mice repopulates the microglial niche and prevents each of these pathological changes. Taken together, these results indicate the protective functions of microglia in reducing CAA, blood-brain barrier dysfunction, and brain calcification. To further understand the clinical implications of these findings, human AD tissue and iPSC-microglia were examined, providing evidence that microglia phagocytose calcium crystals, and this process is impaired by loss of the AD risk gene, TREM2

The Antidote to Zombie Foreclosures: How Bankruptcy Courts Should Address the Zombie Foreclosure Crisis

Bankrupt homeowners across the United States continue to struggle because of the mortgage foreclosure crisis. Although zombie foreclosures present a significant issue for individuals who filed for bankruptcy during the last few years, there is no satisfactory legal remedy. The Bankruptcy Code and bankruptcy courts may offer an overlooked solution to the problem. Due to flexibility within bankruptcy courts, bankruptcy judges have a greater degree of discretion within certain situations to fulfill their equitable powers. Bankruptcy judges can take the realities of the debtor\u27s circumstances into account in ways that state and federal courts cannot. This Comment\u27s recommendations demonstrate the need for both courts and Congress to reconsider the Bankruptcy Code as a solution to zombie foreclosures. With a few amendments, the Bankruptcy Code should be able to help alleviate the zombie foreclosure problem

Development and application of human microglia model to examine the influence of genetic risk factors on microglial function in Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disease for which there is no cure. Worldwide, AD is estimated to effect 50 million people with 10 million new cases each year. Developing therapeutics for Alzheimer’s disease has been particularly difficult given the complex etiology of this disease. Alzheimer’s disease is characterized by an accumulation of parenchymal beta-amyloid protein plaques, tau neurofibrillary tangles, and neuroinflammation. For sporadic AD, which accounts for around 95 % of AD cases, the direct trigger of neurodegeneration remains unclear. Understanding the mechanistic pathophysiology of this disease will allow for the development of more effective targeted therapeutics and biomarker studies to help patients. In the last decade, genome-wide association studies (GWAS) have renewed interest in neuroinflammation as a potential disease-modifying mechanism. These large-scale genetic studies have uncovered a striking enrichment of immune-specific genes as risk-factors for Alzheimer’s disease. However, the function of many of these GWAS loci are not well understood. Additionally, many of these genes have poor homology between human cells and traditional murine disease-models. Thus, there is a critical need to develop a model of human microglia in order to understand how these immune risk factors influence human microglial function. The focus of this dissertation is to develop and characterize a model of human microglia that can be readily studied without the need for isolation of human brain tissue surgically or post-mortem. Building on previous research in the lab, we have developed a model of human microglia differentiated from induced pluripotent stem cells (iPS-Microglia). This model follows developmental ontogeny with a primary differentiation into CD43+ hematopoietic progenitor cells before transition into a microglial differentiation medium containing neuron and astrocyte derived cytokines to educate our microglia in a homeostatic brain-like environment. The result is a highly pure population of iPS-Microglia which perform key microglial functions and cluster alongside human microglial transcriptomes (Chapter 1). Because this microglial model is fully defined beginning from iPS cells, it is possible to combine this approach with modern molecular biological manipulation such as CRISPR gene editing. This dissertation focuses on studies surrounding the AD-risk loci Triggering Receptor Expressed on Myeloid Cells II (TREM2). Predicted loss of function mutations in TREM2 increase Alzheimer’s disease risk up to 2-3 fold making it the highest microglial-specific risk factor for AD. By performing CRISPR-mediated knockout of TREM2 in human iPSCs and differentiating into microglia, we find that TREM2-knockout locks microglia in a homeostatic state. Specifically, microglia lacking TREM2 are deficient in SYK-mediated phagocytosis, CXCR4-mediated migration, and are more sensitive to MCSF-mediated cell death. In vivo, this translates to an inability to perform chemotaxis towards and compaction of beta-amyloid plaques leading to a build-up of pathology in the brain. We also characterize a distinct lack of transcriptional activation in TREM2 knockout cells suggesting that induction of the Disease Associated Microglia (DAM) profile may be an essential immune response in shielding the brain from dementia (Chapter 2). Because TREM2-knockout cells are locked in a homeostatic state, they express high levels of homeostatic microglia markers P2RY12 and P2RY13. These purinergic receptors are critical for microglial communication with neurons and clearance of dead cells. We show that purinergic signaling has a profound effect on microglial motility and process extension and that hyper-expression and response of purinergic signaling in TREM2-knockout microglia may render these cells unable to sense gradients and activate against disease pathology. Furthermore, we highlight that partial inhibition of purinergic receptors will rescue migratory deficits characterized in TREM2-knockout microglia suggesting a therapeutic mechanism (Chapter 3). Taken as a whole, the development of the iPS-Microglia model has yielded critical insight into the interaction of microglial function and the development of Alzheimer’s disease. This model has been readily adapted by many academic labs as well as pharmaceutical companies with the aim of studying human microglial function or other disease risk loci. By further studying AD risk genes in this fashion, we may be able to converge on several mechanisms by which microglial functions are able to attenuate or drive neurodegeneration. Focusing therapeutic efforts on these pathways could lead to the development of immunotherapies for Alzheimer’s disease

Microglia in Alzheimer's Disease: Exploring How Genetics and Phenotype Influence Risk

Research into the function of microglia has dramatically accelerated during the last few years, largely due to recent genetic findings implicating microglia in virtually every neurodegenerative disorder. In Alzheimer's disease (AD), a majority of risk loci discovered through genome-wide association studies were found in or near genes expressed most highly in microglia leading to the hypothesis that microglia play a much larger role in disease progression than previously thought. From this body of work produced in the last several years, we find that almost every function of microglia has been proposed to influence the progression of AD from altered phagocytosis and synaptic pruning to cytokine secretion and changes in trophic support. By studying key Alzheimer's risk genes such as TREM2, CD33, ABCA7, and MS4A6A, we will be able to distinguish true disease-modulatory pathways from the full range of microglial-related functions. To successfully carry out these experiments, more advanced microglial models are needed. Microglia are quite sensitive to their local environment, suggesting the need to more fully recapitulate an in vivo environment to study this highly plastic cell type. Likely only by combining the above approaches will the field fully elucidate the molecular pathways that regulate microglia and influence neurodegeneration, in turn uncovering potential new targets for future therapeutic development