This supplementary research proposal applies the expertise, techniques and hardware developed under the funded parent grant (R01EB025819) to study the contribution of neuronal activity to the pathogenesis of Alzheimer?s disease (AD). AD is a progressive multifactorial neurodegenerative disorder and the major type of dementia. Neuronal activity shows a complex relationship with AD, with (1) neurons and areas susceptible to more intense neuronal activity, clinically hyper-excitable or stimulated intensely exhibiting evidence of AD pathogeny in humans, animal models and cell cultures; and (2) neurons or synapses whose activity is reduced or putatively under-stimulated by lack of cognitive engagement also demonstrating altered prospects as the disease progresses. Since neuroinflammation is one of the central mechanisms in AD pathogenesis and an area currently under intensive research, elucidation of its systemic drivers at the neuronal level and pathogenic impact will provide mechanistic insights on disease progression and uncover intervention principles. We hypothesize that one of key mediators of this nonlinear relationship between neuronal activity and AD is neuroinflammation, because studies independently linked neuroinflammation to both sides of the hypothetical equation AD=f(neuronal activity). Specifically in this application, using an Alzheimer?s-in-a-dish model with neurons- microglia cocultures derived from induced pluripotent stem cells (iPSCs) of AD patients, we aim to determine the electrical parameters that modulate neuroinflammatory response and how this relates to AD progression. Our operational hypothesis is that different patterns of electrical stimulation will nonlinearly affect neuroinflammatory responses in AD neuron-microglia co-cultures, which in turn contributes to the pathogenesis of AD at the neurons? structural and functional levels. To test this hypothesis, we propose to deliver different patterns of electrical stimulation to Alzheimer?s-in-a-dish models and measure cytokine release using cytokine array (Exp. 1), analyze microglia migration behavior with impedimetric monitoring (Exp. 2) and investigate neuronal function electrophysiologically with multielectrode array (MEA) (Exp. 3). This plan is executed by an interdisciplinary team of 4 principle investigators whose skills cover broadly the needs of the research plan, including an expert in the molecular biology of neurodegeneration/regeneration, a roboticist expert in control systems; a biosensor and microfluidic nanoengineer and a complexity neuroscientist expert in electrophysiological spatiotemporal dynamics. This supplement grant is directly focused on investigating AD pathogenesis in the presence of different neuronal stimulation patterns, which resemble physiological or pathological neuroelectric events responding to environmental sources. Our proposed studies, thus well aligned with Milestone 2H outlined in the research implementation plans by National Institute of Aging (NIA), provide a novel in vitro platform with integrated electrical stimulation and cellular components and a broadly integrated analysis toolkit to gain more detailed mechanistic insights on neuronal activity-mediated AD progression.
Alzheimer?s disease (AD) is a multifactorial disease that consists of both genetic and environmental risk factors. Neuronal activity is a convergent target for both environmental and genetic risk factors. The proposed research focuses on the application of our customized action potential generator to study the effect of different electrical stimulation patterns on neuroinflammation in Alzheimer?s-in-a-dish cellular model.
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