2016 — 2017 |
Kim, Jungsu |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Microrna-758-3p in Cognition and Alzheimer's Disease @ Mayo Clinic Jacksonville
? DESCRIPTION (provided by applicant): Mounting evidence suggests that microRNA (miRNA) dysregulation may contribute to psychiatric disorders and neurodegenerative disorders. Although modulations of miRNA function have generated promising clinical data for several diseases, miRNA's role in Alzheimer's disease (AD) has not been investigated thoroughly. Here, we seek to define the role of miR-758 in cognition and Amyloid ? (A?) metabolism. A? peptide is known to impair synaptic functions, contributing to cognitive dysfunction in a manner that depends on the cAMP responsive element binding protein (CREB) signaling pathway. CREB is a transcriptional master regulator of synaptic plasticity and neuronal survival. In support of the notion that dysregulation of CREB is a key event underlying A?-mediated synaptic deficits and memory loss, we found that CREB levels in the frontal cortex of AD patients are dramatically decreased. Activation of the CREB pathway has been shown to confer resistance to A?-mediated synapse loss and restores learning and memory functions in APP transgenic mouse models. Apolipoprotein E (APOE) genotype is the strongest genetic risk factor for AD. Lipidation of ApoE by ATP- binding cassette transporter A1 (ABCA1) is known to facilitate A? clearance. Previously, we demonstrated that only a two-fold overexpression of ABCA1 is sufficient to increase ApoE lipidation and decrease A? accumulation by more than 60% in an APP mouse model. Therefore, identifying regulatory mechanisms of CREB and ABCA1 expression may provide new therapeutic targets for AD. Using unbiased miRNA screening, we identified miR-758 as one of the most significantly upregulated miRNAs by A?42. Most interestingly, miR- 758 expression levels are ~100-fold higher in the brain than in most other organs and our innovative systems biology approach indicates that neuronal function and survival pathways are the most significantly enriched functional groups among miR-758 targets. More specifically, we identified CREB and ABCA1 as direct targets of miR-758. In this application, we propose to investigate the role of miR-758 in cognition and Alzheimer's disease by using primary neuronal cells (Aim 1) and an APP knock-in mouse model (Aim 2). Because APP knock-in mouse model expresses human APP at physiological level under the control of endogenous regulatory sequences, it is an ideal model to study synaptic plasticity affected by A? and CREB. We will determine whether overexpression of miR-758 impairs learning and memory and trigger neuronal cell death by downregulating CREB. If so, this mouse line will be a valuable model system to test neuroprotective therapeutics in vivo, overcoming the lack of overt cell death in most APP transgenic mouse models. We also aim to determine whether inhibition of miR-758 activity can be a novel therapeutic strategy by increasing CREB and ABCA1 levels. Collectively, this work will facilitate our understanding of microRNAs in cognitive function and A? metabolism and may spur further interest in non-coding RNAs and other epigenetic factors.
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0.96 |
2016 — 2020 |
Kim, Jungsu |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Microrna-33 in Alzheimer's Disease @ Mayo Clinic Jacksonville
PROJECT SUMMARY/ABSTRACT Mounting evidence suggests that microRNA (miRNA) dysregulation may contribute to psychiatric disorders and neurodegenerative disorders. Although modulations of miRNA function have generated promising clinical data for several diseases, miRNA?s role in Alzheimer?s disease (AD) has not been investigated thoroughly. Apolipoprotein E (ApoE) genotype is the strongest genetic risk factor for AD. In addition to ApoE isoform, alterations in ApoE levels and lipidation status have been shown to influence A? aggregation. We and others reported the critical roles of ATP-binding cassette transporter A1 (ABCA1) in regulating ApoE lipidation and A? levels in the brain and its therapeutic potential. Increasing evidence suggests that neuroinflammation plays a critical role in AD pathogenesis. Therefore, targeting inflammatory pathways is an emerging therapeutic strategy, along with the direct targeting of ApoE/A? pathway, for AD therapy. Recently, we found that miR-33 gene deletion significantly increases ABCA1 levels and soluble A? clearance, leading to reduction of soluble A? levels in the brain of APP/PS1 mouse model. We also identified that miR-33 regulates neuroinflammation by directly targeting transforming growth factor ? (TGF?) receptor 1 (TGF?R1) gene. Here, we now seek to define the role of miR-33 in ApoE and Amyloid ? (A?) metabolism in mice (Aim 1) and neuroinflammation (Aim 2). In Aim 1, we will use ABCA1 knockout and ApoE knockout mice along with miR-33 knockout mouse models. In Aim 2, we will use TGF?R1 knockout mouse model. Importantly, we demonstrated that antisense oligonucleotide (ASO)-based pharmacological inhibition of miR-33 efficiently increases ABCA1 levels and reduces soluble A? levels in the brain. In Aim 3, we will assess the effect of long-term treatment of anti-miR-33 ASO on A? deposition, neuroinflammation, and behavior in mice. We will assess the preventive and therapeutic effect by treating anti-miR-33 ASO before and after the development of A? plaques and memory deficits in APP/PS1 mice.
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0.96 |
2016 — 2020 |
Kim, Jungsu |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Ldlr in Regulating Metabolism of Apolipoprotein E and Amyloid-Beta @ Mayo Clinic Jacksonville
PROJECT SUMMARY/ABSTRACT Apolipoprotein E (ApoE) genotype is the strongest genetic risk factor for Alzheimer?s disease (AD). Prevailing evidence suggests that ApoE isoforms affect amyloid ? (A?), tau, neuroinflammation, and synaptic plasticity. In addition to isoforms, alteration in ApoE protein levels has been shown to influence neuroinflammation and A? clearance. Previously, we reported the critical roles of ApoE receptor, low density lipoprotein receptor (LDLR), in regulating ApoE clearance and A? levels in the brain. Overexpression of LDLR in the brain dramatically inhibits amyloid formation by decreasing ApoE level and increasing A? clearance. These beneficial effects were seen with as little as just 2-fold over-expression of LDLR. However, translating these observations into therapy has been hampered by a poor understanding of cellular and molecular mechanism and a paucity of effective approach to regulate the levels of LDLR in the brain. To overcome this critical barrier, we propose to investigate cellular mechanism by which Inducible Degrader Of LDLR (IDOL) regulates LDLR, ApoE, A?, and tau. In collaboration with Dr. Tontonoz (HHMI, UCLA), we found that global deletion of IDOL gene dramatically increases LDLR levels and decreases apoE levels in the brain. IDOL is an E3 ubiquitin ligase that ubiquitinates LDLR and targets it for degradation. Importantly, loss of IDOL expression significantly reduced amyloid plaque burden and ameliorated neuroinflammation in an AD mouse model. Based on these strong preliminary data, we now propose to determine the cellular and molecular mechanism by which IDOL affects ApoE and A? using primary cells isolated from global and conditional knockout IDOL mouse model. We hypothesize that the beneficial effect of IDOL deletion is mediated through LDLR-mediated ApoE level reduction and ApoER2- mediated Reelin signaling. To test hour hypothesis, we will apply innovative methods, such as molecular dynamics simulation, in vivo stable isotope pulse chase mass spectrometry, and in vivo A? and cytokines microdialysis. Deciphering IDOL pathway in cellular details may help better understanding ApoE signaling in basic biology and AD.
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0.96 |
2016 — 2020 |
Kim, Jungsu |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The Role of Aging-Associated Micrornas in Alzheimer's Disease @ Mayo Clinic Jacksonville
PROJECT SUMMARY/ABSTRACT Mounting evidence suggests that epigenetic changes, including microRNA (miRNA) dysregulation, contribute to aging, psychiatric disorders and neurodegenerative disorders. Although modulations of miRNA function have generated promising clinical data for several diseases, miRNA?s roles in brain aging and Alzheimer?s disease (AD) have not been investigated thoroughly. During AD pathogenesis, dysregulation of insulin signaling is evident. Abnormal accumulation of Tau and amyloid beta is hypothesized to initiate a pathogenic cascade leading to AD. Given the critical role of these protein aggregations in AD, strategies to modulate tau and amyloid beta are actively being pursued as therapies. Toward that end, we seek to define the role of microRNAs (miRNAs), specifically miR-17-92, in AD pathogenesis. Instead of setting up a hypothesis based on the previously well-known proteins and concepts, we performed unbiased transcriptomics profiling experiments and identified miR-17-92 as the most strongly dysregulated miRNAs during brain aging. Remarkably, our finding is consistent with a recent landmark study by the NIH Common Fund?s Genotype-Tissue Expression (GTEx) consortium?s data using 11 human brain subregions. We hypothesize that such dysregulation of miR- 17-92 expression may directly contribute to aging process. Therefore, it will be critical to understand the functional effect of miR-17-92 decline on brain aging and try to restore its levels to ameliorate aging effect and AD pathogenesis. Mounting studies recently suggests that miRNA dysregulation may contribute to several neurodegenerative disorders, including AD. Interestingly, we found that miR-17-92 regulates tau phosphorylation and APP expression level possibly by modulating insulin signaling pathway. In this application, we propose to investigate the role of miR-17-92 in cognition and Alzheimer?s disease. We will determine how miR-17-92 affects learning and memory and AD-related neuropathology using novel AAV Tau mouse model and APP knock-in mouse model. Furthermore using several innovative in vivo methods, we will investigate the mechanism underlying the role of miR-17-92 in Tau and Abeta metabolism.
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0.96 |