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Dysregulated Neuroimmune Interaction...

Boreland, Andrew James,

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Dysregulated Neuroimmune Interactions in Human Stem Cell Derived Neural Models /

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Dysregulated Neuroimmune Interactions in Human Stem Cell Derived Neural Models // Andrew James Boreland.
作者:	Boreland, Andrew James,
面頁冊數:	1 electronic resource (147 pages)
附註:	Source: Dissertations Abstracts International, Volume: 86-05, Section: B.
Contained By:	Dissertations Abstracts International86-05B.
標題:	Neurosciences. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31143909
ISBN:	9798342759045

Dysregulated Neuroimmune Interactions in Human Stem Cell Derived Neural Models /
Boreland, Andrew James,

Dysregulated Neuroimmune Interactions in Human Stem Cell Derived Neural Models /Andrew James Boreland. - 1 electronic resource (147 pages)

Source: Dissertations Abstracts International, Volume: 86-05, Section: B.

Dementia is a debilitating neurodegenerative condition with the highest economic burden of all adult neurological disorders. While the cellular mechanisms underlying dementia-related pathology remain enigmatic, inflammation likely plays a major role in causing and exacerbating dementia-related neurodegeneration and cognitive decline. Chronic neuroinflammation is a hallmark of both alcohol use disorder (AUD)-related dementia and Human Immunodeficiency Virus-1 (HIV-1) related dementia. In this dissertation, I first addressed the need for human in vitro neuroimmune models by generating and combining human stem cell derived microglia, neurons, and astrocytes in two model systems. Second, I then interrogated the consequences of HIV-1 infection on human stem cell derived microglia and cerebral organoids. I found that HIV-1 productively infects iPSC-derived microglia and triggers inflammatory activation, resulting in sustained type I interferon signaling that persists in both microglia monoculture and in microglia-containing cerebral organoids. These data are consistent with recent studies suggesting a role for chronic interferon signaling in cognitive deficits and neurodegeneration. Third, I investigated the neuroinflammatory consequences of ethanol exposure on a microglia, neuron, and astrocyte tri-culture model. We found ethanol exposure leads to widespread inflammatory gene expression, activation of the NLRP3 inflammasome, microglia activation, and potent upregulation and alternative splicing of TREM2. These data suggest a complex role for ethanol in the dysregulation of neuroimmune interactions among microglia, astrocytes, and neurons. Our findings relating to TREM2, elevation of complement cascade proteins, and microglial activation point to possible alterations in synaptic connectivity and transmission. Overall, these results expand our understanding of underlying inflammatory processes incited by either HIV-1 or ethanol, both of which are known contributors to dementia, and offers new human neuroimmune models for therapeutic discovery.

English

ISBN: 9798342759045Subjects--Topical Terms:

588700
Neurosciences.
Subjects--Index Terms:

Human Immunodeficiency Virus-1

Dysregulated Neuroimmune Interactions in Human Stem Cell Derived Neural Models /
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520 $a Dementia is a debilitating neurodegenerative condition with the highest economic burden of all adult neurological disorders. While the cellular mechanisms underlying dementia-related pathology remain enigmatic, inflammation likely plays a major role in causing and exacerbating dementia-related neurodegeneration and cognitive decline. Chronic neuroinflammation is a hallmark of both alcohol use disorder (AUD)-related dementia and Human Immunodeficiency Virus-1 (HIV-1) related dementia. In this dissertation, I first addressed the need for human in vitro neuroimmune models by generating and combining human stem cell derived microglia, neurons, and astrocytes in two model systems. Second, I then interrogated the consequences of HIV-1 infection on human stem cell derived microglia and cerebral organoids. I found that HIV-1 productively infects iPSC-derived microglia and triggers inflammatory activation, resulting in sustained type I interferon signaling that persists in both microglia monoculture and in microglia-containing cerebral organoids. These data are consistent with recent studies suggesting a role for chronic interferon signaling in cognitive deficits and neurodegeneration. Third, I investigated the neuroinflammatory consequences of ethanol exposure on a microglia, neuron, and astrocyte tri-culture model. We found ethanol exposure leads to widespread inflammatory gene expression, activation of the NLRP3 inflammasome, microglia activation, and potent upregulation and alternative splicing of TREM2. These data suggest a complex role for ethanol in the dysregulation of neuroimmune interactions among microglia, astrocytes, and neurons. Our findings relating to TREM2, elevation of complement cascade proteins, and microglial activation point to possible alterations in synaptic connectivity and transmission. Overall, these results expand our understanding of underlying inflammatory processes incited by either HIV-1 or ethanol, both of which are known contributors to dementia, and offers new human neuroimmune models for therapeutic discovery.
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