Characterizing noncanonical cellular pathways underlying alzheimer's disease

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Culibrk, Robert, Alan
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Biomedical engineering
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Late-onset Alzheimer’s Disease (LOAD) is a devastating neurodegenerative disorder that causes significant cognitive debilitation in tens of millions of patients worldwide. Throughout disease progression in a significant subset of LOAD patients, abnormal secretase activity results in the aberrant cleavage and subsequent aggregation of neurotoxic amyloid-beta (Αβ) plaques in the cerebral extracellular space and hyperphosphorylation and destabilization of structural tau proteins surrounding neuronal microtubules. Both pathologies are correlated with the propagation of a disease-associated subset of microglia – the principal immune cells of the brain – characterized by distinctively pro-inflammatory cytokine secretion and inhibited AD substrate uptake capacity, which together further contribute to neuronal degeneration. For decades, chronic neuroinflammation has been purported as one of the cardinal pathophysiological driving features of AD; however, despite several works postulating the underlying mechanisms of inflammation-mediated neurodegeneration, its pathogenesis, and its relation to the inception of cognitive impairment, remain elusive. Moreover, the limited clinical success of treatments targeting these specific pathological features in the central nervous system (CNS) illustrates the need to investigate alternative approaches for ameliorating AD outcomes. Accumulating preclinical and clinical evidence suggests that dysregulation in the following categories of intrinsic cellular stress resistance mechanisms is involved in the pathogenesis and progression of Alzheimer’s disease: neuronal autophagic homeostasis, epigenetic regulation, and redox balance. Furthermore, while AD was previously apprehended as a condition relegated to the CNS, multiple retrospective analyses report that peripheral chronic inflammatory conditions, including osteoporosis, may exacerbate inflammatory neurodegeneration and accelerate AD progression. Toward achieving a more holistic understanding of AD as a systemic disorder involving mechanisms beyond those currently considered canonical, we first sought to interrogate the processes underlying sympathetic hyperactivity-mediated osteopenia by implementing the sympathetic neuron (SN)-like rat neuroendocrine pheochromocytoma-12 (PC12) cell line in 3D transwell coculture with human mesenchymal stem cells (hMSCs), in the presence of an AD-analogous inflammatory environment. We then characterized alterations in a subset of the intrinsic cellular mechanisms which significantly contribute to AD related neuronal deficits by comparing iPSC-differentiated cortical neurons derived from an AD patient to those derived from an age- and sex-matched healthy control. A subset of AD-derived neurons was treated with the P2 purinergic receptor antagonist suramin to evaluate the putative role of extracellular adenosine triphosphate (ATP) signaling in neuronal pathology. Finally, we further probed the involvement of intrinsic neuronal mechanisms found to be dysregulated in an expanded panel of AD derived, iPSC-differentiated cortical neurons in the context of two hypothesized risk factors for AD development: hyperhomocysteinemia and environmental toxin exposure.
School of Engineering
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Rensselaer Polytechnic Institute, Troy, NY
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