Yoo Jin Jung

All Publications

• Role of chronic neuroinflammation in neuroplasticity and cognitive function: A hypothesis. Alzheimer's & dementia : the journal of the Alzheimer's Association Lecca, D., Jung, Y. J., Scerba, M. T., Hwang, I., Kim, Y. K., Kim, S., Modrow, S., Tweedie, D., Hsueh, S., Liu, D., Luo, W., Glotfelty, E., Li, Y., Wang, J., Luo, Y., Hoffer, B. J., Kim, D. S., McDevitt, R. A., Greig, N. H. 2022

  Abstract

  OBJECTIVE: Evaluating the efficacy of 3,6'-dithioPomalidomide in 5xFAD Alzheimer's disease (AD) mice to test the hypothesis that neuroinflammation is directly involved in the development of synaptic/neuronal loss and cognitive decline.BACKGROUND: Amyloid-beta (Abeta) or tau-focused clinical trials have proved unsuccessful in mitigating AD-associated cognitive impairment. Identification of new drug targets is needed. Neuroinflammation is a therapeutic target in neurodegenerative disorders, and TNF-alpha a pivotal neuroinflammatory driver.NEW HYPOTHESIS: AD-associated chronic neuroinflammation directly drives progressive synaptic/neuronal loss and cognitive decline. Pharmacologically mitigating microglial/astrocyte activation without altering Abeta generation will define the role of neuroinflammation in AD progression.MAJOR CHALLENGES: Difficulty of TNF-alpha-lowering compounds reaching brain, and identification of a therapeutic-time window to preserve the beneficial role of neuroinflammatory processes.LINKAGE TO OTHER MAJOR THEORIES: Microglia/astroglia are heavily implicated in maintenance of synaptic plasticity/function in healthy brain and are disrupted by Abeta. Mitigation of chronic gliosis can restore synaptic homeostasis/cognitive function.

  View details for DOI 10.1002/alz.12610

  View details for PubMedID 35234334

• Repurposing Immunomodulatory Imide Drugs (IMiDs) in Neuropsychiatric and Neurodegenerative Disorders. Frontiers in neuroscience Jung, Y. J., Tweedie, D., Scerba, M. T., Kim, D. S., Palmas, M. F., Pisanu, A., Carta, A. R., Greig, N. H. 2021; 15: 656921

  Abstract

  Neuroinflammation represents a common trait in the pathology and progression of the major psychiatric and neurodegenerative disorders. Neuropsychiatric disorders have emerged as a global crisis, affecting 1 in 4 people, while neurological disorders are the second leading cause of death in the elderly population worldwide (WHO, 2001; GBD 2016 Neurology Collaborators, 2019). However, there remains an immense deficit in availability of effective drug treatments for most neurological disorders. In fact, for disorders such as depression, placebos and behavioral therapies have equal effectiveness as antidepressants. For neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, drugs that can prevent, slow, or cure the disease have yet to be found. Several non-traditional avenues of drug target identification have emerged with ongoing neurological disease research to meet the need for novel and efficacious treatments. Of these novel avenues is that of neuroinflammation, which has been found to be involved in the progression and pathology of many of the leading neurological disorders. Neuroinflammation is characterized by glial inflammatory factors in certain stages of neurological disorders. Although the meta-analyses have provided evidence of genetic/proteomic upregulation of inflammatory factors in certain stages of neurological disorders. Although the mechanisms underpinning the connections between neuroinflammation and neurological disorders are unclear, and meta-analysis results have shown high sensitivity to factors such as disorder severity and sample type, there is significant evidence of neuroinflammation associations across neurological disorders. In this review, we summarize the role of neuroinflammation in psychiatric disorders such as major depressive disorder, generalized anxiety disorder, post-traumatic stress disorder, and bipolar disorder, as well as in neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease, and introduce current research on the potential of immunomodulatory imide drugs (IMiDs) as a new treatment strategy for these disorders.

  View details for DOI 10.3389/fnins.2021.656921

  View details for PubMedID 33854417

• Neuroinflammation as a Factor of Neurodegenerative Disease: Thalidomide Analogs as Treatments FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY Jung, Y., Tweedie, D., Scerba, M. T., Greig, N. H. 2019; 7: 313

  Abstract

  Neuroinflammation is initiated when glial cells, mainly microglia, are activated by threats to the neural environment, such as pathogen infiltration or neuronal injury. Although neuroinflammation serves to combat these threats and reinstate brain homeostasis, chronic inflammation can result in excessive cytokine production and cell death if the cause of inflammation remains. Overexpression of tumor necrosis factor-α (TNF-α), a proinflammatory cytokine with a central role in microglial activation, has been associated with neuronal excitotoxicity, synapse loss, and propagation of the inflammatory state. Thalidomide and its derivatives, termed immunomodulatory imide drugs (IMiDs), are a class of drugs that target the 3'-untranslated region (3'-UTR) of TNF-α mRNA, inhibiting TNF-α production. Due to their multi-potent effects, several IMiDs, including thalidomide, lenalidomide, and pomalidomide, have been repurposed as drug treatments for diseases such as multiple myeloma and psoriatic arthritis. Preclinical studies of currently marketed IMiDs, as well as novel IMiDs such as 3,6'-dithiothalidomide and adamantyl thalidomide derivatives, support the development of IMiDs as therapeutics for neurological disease. IMiDs have a competitive edge compared to similar anti-inflammatory drugs due to their blood-brain barrier permeability and high bioavailability, with the potential to alleviate symptoms of neurodegenerative disease and slow disease progression. In this review, we evaluate the role of neuroinflammation in neurodegenerative diseases, focusing specifically on the role of TNF-α in neuroinflammation, as well as appraise current research on the potential of IMiDs as treatments for neurological disorders.

  View details for DOI 10.3389/fcell.2019.00313

  View details for Web of Science ID 000514114500001

  View details for PubMedID 31867326

  View details for PubMedCentralID PMC6904283

• Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes. Proceedings of the National Academy of Sciences of the United States of America Le Guen, Y., Luo, G., Ambati, A., Damotte, V., Jansen, I., Yu, E., Nicolas, A., de Rojas, I., Peixoto Leal, T., Miyashita, A., Bellenguez, C., Lian, M. M., Parveen, K., Morizono, T., Park, H., Grenier-Boley, B., Naito, T., Küçükali, F., Talyansky, S. D., Yogeshwar, S. M., Sempere, V., Satake, W., Alvarez, V., Arosio, B., Belloy, M. E., Benussi, L., Boland, A., Borroni, B., Bullido, M. J., Caffarra, P., Clarimon, J., Daniele, A., Darling, D., Debette, S., Deleuze, J. F., Dichgans, M., Dufouil, C., During, E., Düzel, E., Galimberti, D., Garcia-Ribas, G., García-Alberca, J. M., García-González, P., Giedraitis, V., Goldhardt, O., Graff, C., Grünblatt, E., Hanon, O., Hausner, L., Heilmann-Heimbach, S., Holstege, H., Hort, J., Jung, Y. J., Jürgen, D., Kern, S., Kuulasmaa, T., Lee, K. H., Lin, L., Masullo, C., Mecocci, P., Mehrabian, S., de Mendonça, A., Boada, M., Mir, P., Moebus, S., Moreno, F., Nacmias, B., Nicolas, G., Niida, S., Nordestgaard, B. G., Papenberg, G., Papma, J., Parnetti, L., Pasquier, F., Pastor, P., Peters, O., Pijnenburg, Y. A., Piñol-Ripoll, G., Popp, J., Porcel, L. M., Puerta, R., Pérez-Tur, J., Rainero, I., Ramakers, I., Real, L. M., Riedel-Heller, S., Rodriguez-Rodriguez, E., Ross, O. A., Luís Royo, J., Rujescu, D., Scarmeas, N., Scheltens, P., Scherbaum, N., Schneider, A., Seripa, D., Skoog, I., Solfrizzi, V., Spalletta, G., Squassina, A., van Swieten, J., Sánchez-Valle, R., Tan, E. K., Tegos, T., Teunissen, C., Thomassen, J. Q., Tremolizzo, L., Vyhnalek, M., Verhey, F., Waern, M., Wiltfang, J., Zhang, J., Zetterberg, H., Blennow, K., He, Z., Williams, J., Amouyel, P., Jessen, F., Kehoe, P. G., Andreassen, O. A., Van Duin, C., Tsolaki, M., Sánchez-Juan, P., Frikke-Schmidt, R., Sleegers, K., Toda, T., Zettergren, A., Ingelsson, M., Okada, Y., Rossi, G., Hiltunen, M., Gim, J., Ozaki, K., Sims, R., Foo, J. N., van der Flier, W., Ikeuchi, T., Ramirez, A., Mata, I., Ruiz, A., Gan-Or, Z., Lambert, J. C., Greicius, M. D., Mignot, E. 2023; 120 (36): e2302720120

  Abstract

  Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

  View details for DOI 10.1073/pnas.2302720120

  View details for PubMedID 37643212

• Zebrafish Blunt-Force TBI Induces Heterogenous Injury Pathologies That Mimic Human TBI and Responds with Sonic Hedgehog-Dependent Cell Proliferation across the Neuroaxis BIOMEDICINES Hentig, J., Cloghessy, K., Lahne, M., Jung, Y., Petersen, R. A., Morris, A. C., Hyde, D. R. 2021; 9 (8)

  Abstract

  Blunt-force traumatic brain injury (TBI) affects an increasing number of people worldwide as the range of injury severity and heterogeneity of injury pathologies have been recognized. Most current damage models utilize non-regenerative organisms, less common TBI mechanisms (penetrating, chemical, blast), and are limited in scalability of injury severity. We describe a scalable blunt-force TBI model that exhibits a wide range of human clinical pathologies and allows for the study of both injury pathology/progression and mechanisms of regenerative recovery. We modified the Marmarou weight drop model for adult zebrafish, which delivers a scalable injury spanning mild, moderate, and severe phenotypes. Following injury, zebrafish display a wide range of severity-dependent, injury-induced pathologies, including seizures, blood-brain barrier disruption, neuroinflammation, edema, vascular injury, decreased recovery rate, neuronal cell death, sensorimotor difficulties, and cognitive deficits. Injury-induced pathologies rapidly dissipate 4-7 days post-injury as robust cell proliferation is observed across the neuroaxis. In the cerebellum, proliferating nestin:GFP-positive cells originated from the cerebellar crest by 60 h post-injury, which then infiltrated into the granule cell layer and differentiated into neurons. Shh pathway genes increased in expression shortly following injury. Injection of the Shh agonist purmorphamine in undamaged fish induced a significant proliferative response, while the proliferative response was inhibited in injured fish treated with cyclopamine, a Shh antagonist. Collectively, these data demonstrate that a scalable blunt-force TBI to adult zebrafish results in many pathologies similar to human TBI, followed by recovery, and neuronal regeneration in a Shh-dependent manner.

  View details for DOI 10.3390/biomedicines9080861

  View details for Web of Science ID 000688873200001

  View details for PubMedID 34440066

  View details for PubMedCentralID PMC8389629

• 3,6 '-dithiopomalidomide reduces neural loss, inflammation, behavioral deficits in brain injury and microglial activation ELIFE Lin, C., Lecca, D., Yang, L., Luo, W., Scerba, M. T., Tweedie, D., Huang, P., Jung, Y., Kim, D., Yang, C., Hoffer, B. J., Wang, J., Greig, N. H. 2020; 9

  Abstract

  Traumatic brain injury (TBI) causes mortality and disability worldwide. It can initiate acute cell death followed by secondary injury induced by microglial activation, oxidative stress, inflammation and autophagy in brain tissue, resulting in cognitive and behavioral deficits. We evaluated a new pomalidomide (Pom) analog, 3,6'-dithioPom (DP), and Pom as immunomodulatory agents to mitigate TBI-induced cell death, neuroinflammation, astrogliosis and behavioral impairments in rats challenged with controlled cortical impact TBI. Both agents significantly reduced the injury contusion volume and degenerating neuron number evaluated histochemically and by MRI at 24 hr and 7 days, with a therapeutic window of 5 hr post-injury. TBI-induced upregulated markers of microglial activation, astrogliosis and the expression of pro-inflammatory cytokines, iNOS, COX-2, and autophagy-associated proteins were suppressed, leading to an amelioration of behavioral deficits with DP providing greater efficacy. Complementary animal and cellular studies demonstrated DP and Pom mediated reductions in markers of neuroinflammation and α-synuclein-induced toxicity.

  View details for DOI 10.7554/eLife.54726

  View details for Web of Science ID 000555011500001

  View details for PubMedID 32589144

  View details for PubMedCentralID PMC7375814

• The p53 inactivators pifithrin-mu and pifithrin-alpha mitigate TBI-induced neuronal damage through regulation of oxidative stress, neuroinflammation, autophagy and mitophagy EXPERIMENTAL NEUROLOGY Yang, L., Greig, N. H., Tweedie, D., Jung, Y., Chiang, Y., Hoffer, B. J., Miller, J. P., Chang, K., Wang, J. 2020; 324: 113135

  Abstract

  Traumatic brain injury (TBI) is one of the most common causes of death and disability worldwide. We investigated whether inhibition of p53 using pifithrin (PFT)-α or PFT-μ provides neuroprotective effects via p53 transcriptional dependent or -independent mechanisms, respectively. Sprague Dawley rats were subjected to controlled cortical impact TBI followed by the administration of PFTα or PFT-μ (2 mg/kg, i.v.) at 5 h after TBI. Brain contusion volume, as well as sensory and motor functions were evaluated at 24 h after TBI. TBI-induced impairments were mitigated by both PFT-α and PFT-μ. Fluoro-Jade C staining was used to label degenerating neurons within the TBI-induced cortical contusion region that, together with Annexin V positive neurons, were reduced by PFT-μ. Double immunofluorescence staining similarly demonstrated that PFT-μ significantly increased HO-1 positive neurons and mRNA expression in the cortical contusion region as well as decreased numbers of 4-hydroxynonenal (4HNE)-positive cells. Levels of mRNA encoding for p53, autophagy, mitophagy, anti-oxidant, anti-inflammatory related genes and proteins were measured by RT-qPCR and immunohistochemical staining, respectively. PFT-α, but not PFT-μ, significantly lowered p53 mRNA expression. Both PFT-α and PFT-μ lowered TBI-induced pro-inflammatory cytokines (IL-1β and IL-6) mRNA levels as well as TBI-induced autophagic marker localization (LC3 and p62). Finally, treatment with PFT-μ mitigated TBI-induced declines in mRNA levels of PINK-1 and SOD2. Our data suggest that both PFT-μ and PFT-α provide neuroprotective actions through regulation of oxidative stress, neuroinflammation, autophagy, and mitophagy mechanisms, and that PFT-μ, in particular, holds promise as a TBI treatment strategy.

  View details for DOI 10.1016/j.expneurol.2019.113135

  View details for Web of Science ID 000509423400011

  View details for PubMedID 31778663

  View details for PubMedCentralID PMC7792017

• (-)-Phenserine and the prevention of pre-programmed cell death and neuroinflammation in mild traumatic brain injury and Alzheimer's disease challenged mice NEUROBIOLOGY OF DISEASE Lecca, D., Bader, M., Tweedie, D., Hoffman, A. F., Jung, Y., Hsueh, S., Hoffer, B. J., Becker, R. E., Pick, C. G., Lupica, C. R., Greig, N. H. 2019; 130: 104528

  Abstract

  Mild traumatic brain injury (mTBI) is a risk factor for neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). TBI-derived neuropathologies are promoted by inflammatory processes: chronic microgliosis and release of pro-inflammatory cytokines that further promote neuronal dysfunction and loss. Herein, we evaluated the effect on pre-programmed cell death/neuroinflammation/synaptic integrity and function of (-)-Phenserine tartrate (Phen), an agent originally developed for AD. This was studied at two clinically translatable doses (2.5 and 5.0 mg/kg, BID), in a weight drop (concussive) mTBI model in wild type (WT) and AD APP/PSEN1 transgenic mice. Phen mitigated mTBI-induced cognitive impairment, assessed by Novel Object Recognition and Y-maze behavioral paradigms, in WT mice. Phen fully abated mTBI-induced neurodegeneration, evaluated by counting Fluoro-Jade C-positive (FJC+) cells, in hippocampus and cortex of WT mice. In APP/PSEN1 mice, degenerating cell counts were consistently greater across all experimental groups vs. WT mice. mTBI elevated FJC+ cell counts vs. the APP/PSEN1 control (sham) group, and Phen similarly mitigated this. Anti-inflammatory effects on microglial activation (IBA1-immunoreactivity (IR)) and the pro-inflammatory cytokine TNF-α were evaluated. mTBI increased IBA1-IR and TNF-α/IBA1 colocalization vs. sham, both in WT and APP/PSEN1 mice. Phen decreased IBA1-IR throughout hippocampi and cortices of WT mice, and in cortices of AD mice. Phen, likewise, reduced levels of IBA1/TNF-α-IR colocalization volume across all areas in WT animals, with a similar trend in APP/PSEN1 mice. Actions on astrocyte activation by mTBI were followed by evaluating GFAP, and were similarly mitigated by Phen. Synaptic density was evaluated by quantifying PSD-95+ dendritic spines and Synaptophysin (Syn)-IR. Both were significantly reduced in mTBI vs. sham in both WT and APP/PSEN1 mice. Phen fully reversed the PSD-95+ spine loss in WT and Syn-IR decrease in both WT and APP/PSEN1 mice. To associate immunohistochemical changes in synaptic markers with function, hippocampal long term potentiation (LTP) was induced in WT mice. LTP was impaired by mTBI, and this impairment was mitigated by Phen. In synopsis, clinically translatable doses of Phen ameliorated mTBI-mediated pre-programmed cell death/neuroinflammation/synaptic dysfunction in WT mice, consistent with fully mitigating mTBI-induced cognitive impairments. Phen additionally demonstrated positive actions in the more pathologic brain microenvironment of AD mice, further supporting consideration of its repurposing as a treatment for mTBI.

  View details for DOI 10.1016/j.nbd.2019.104528

  View details for Web of Science ID 000481565000036

  View details for PubMedID 31295555

  View details for PubMedCentralID PMC6716152