All ETDs from UAB

Advisory Committee Chair

Talene Acoubian

Advisory Committee Members

Farah Lubin

Lori L McMahon

Erik D Roberson

David Standaert

Document Type

Dissertation

Date of Award

2023

Degree Name by School

Doctor of Philosophy (PhD) School of Medicine

Abstract

Dysregulation of long non-coding RNAs (lncRNAs) is increasingly associated with cognitive dysfunction and neurodegenerative disorders such as Alzheimer’s disease (AD). The highly evolutionarily conserved lncRNA Nuclear-Enriched Abundant Transcript 1 (NEAT1) is expressed not only in a tissue- and temporally-specific manner, but also celltype specific manner. Despite the predominance of NEAT1 in glial populations, and the significant role astrocytes play in memory, relatively little is known about Neat1 regulation of astrocyte transcriptomics during age-related memory. Here, we report a crucial role of the lncRNA Neat1 in astrocyte dysfunction and memory deficits associated with both normal aging and AD. Expression of Neat1 is increased in hippocampal astrocytes with age as well as in a human transgenic APP-J20 (J20) mouse model of AD. Interestingly, increased expression of Neat1 in astrocytes was observed in male, but not female, J20 mice, a sexual dimorphism that was not observed in normal aging. In J20 mice, this sex-specific increase in Neat1 corresponded with increased seizure susceptibility in J20 male mice; however, Neat1 knockdown in J20 male mice did not alter seizure threshold. Reducing Neat1 expression in the dorsal area CA1 of the hippocampus (dCA1) in J20 mice significantly improved hippocampus-dependent memory while simultaneously reducing astrocyte reactivity markers, suggesting that Neat1 overexpression is associated with iv astrocyte dysfunction in AD. We also found that decreasing astrocytic specific Neat1 in dCA1 is sufficient to improve hippocampus dependent memory in aged animals. Interestingly, increased astrocytic Neat1 appears to mediate cognitive dysfunction through different mechanisms in age and AD. Mimicking age-related overexpression of Neat1 in hippocampal astrocytes results in decreased DNA methylation and increased expression of the potassium channel Kcnj10, but no change in the molecular markers of astrocyte reactivity. These findings suggest that age-related increases in astrocytic Neat1 facilitates cognitive deficits through regulation of potassium homeostasis, while AD-associated memory impairment is associated with Neat1 mediated astrocyte reactivity. Taken together, this work makes a novel contribution to our understanding of how epigenetic regulation by lncRNAs such as Neat1 can drive cell-type specific function underlying memory formation.

Available for download on Sunday, September 01, 2024

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