Jungsu Kim

Publications (31) View all

• Article: Normal cognition in transgenic BRI2-Abeta mice.

  Jungsu Kim, Paramita Chakrabarty, Amanda Hanna, Amelia March, Dennis W Dickson, David R Borchelt, Todd Golde, Christopher Janus
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  ABSTRACT: BACKGROUND: Recent research in Alzheimer's disease (AD) field has been focused on the potential role of the amyloid-beta protein that is derived from the transmembrane amyloid precursor protein (APP) in directly mediating cognitive impairment in AD. Transgenic mouse models overexpressing APP develop robust AD-like amyloid pathology in the brain and show various levels of cognitive decline. In the present study, we examined the cognition of the BRI2-Abeta transgenic mouse model in which secreted extracellular Abeta1-40, Abeta1-42 or both Abeta1-40/Abeta1-42 peptides are generated from the BRI-Abeta fusion proteins encoded by the transgenes. BRI2-Abeta mice produce high levels of Abeta peptides and BRI2-Abeta1-42 mice develop amyloid pathology that is similar to the pathology observed in mutant human APP transgenic models. RESULTS: Using established behavioral tests that reveal deficits in APP transgenic models, BRI2-Abeta1-42 mice showed completely intact cognitive performance at ages both pre and post amyloid plaque formation. BRI2-Abeta mice producing Abeta1-40 or both peptides were also cognitively intact. CONCLUSIONS: These data indicate that high levels of Abeta1-40 or Abeta1-42, or both produced in the absence of APP overexpression do not reproduce memory deficits observed in APP transgenic mouse models. This outcome is supportive of recent data suggesting that APP processing derivatives or the overexpression of full length APP may contribute to cognitive decline in APP transgenic mouse models. Alternatively, at Abeta aggregates may impact cognition by a mechanism that is not fully recapitulated in these BRI2-Abeta mouse models.
  Molecular Neurodegeneration 05/2013; 8(1):15. · 4.28 Impact Factor
• Article: Blocking the Interaction between Apolipoprotein E and Aβ Reduces Intraneuronal Accumulation of Aβ and Inhibits Synaptic Degeneration.

  Magdalena A Kuszczyk, Sandrine Sanchez, Joanna Pankiewicz, Jungsu Kim, Malgorzata Duszczyk, Maitea Guridi, Ayodeji A Asuni, Patrick M Sullivan, David M Holtzman, Martin J Sadowski
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  ABSTRACT: Accumulation of β-amyloid (Aβ) in the brain is a key event in Alzheimer disease pathogenesis. Apolipoprotein (apo) E is a lipid carrier protein secreted by astrocytes, which shows inherent affinity for Aβ and has been implicated in the receptor-mediated Aβ uptake by neurons. To characterize apoE involvement in the intraneuronal Aβ accumulation and to investigate whether blocking the apoE/Aβ interaction could reduce intraneuronal Aβ buildup, we used a noncontact neuronal-astrocytic co-culture system, where synthetic Aβ peptides were added into the media without or with cotreatment with Aβ12-28P, which is a nontoxic peptide antagonist of apoE/Aβ binding. Compared with neurons cultured alone, intraneuronal Aβ content was significantly increased in neurons co-cultured with wild-type but not with apoE knockout (KO) astrocytes. Neurons co-cultured with astrocytes also showed impaired intraneuronal degradation of Aβ, increased level of intraneuronal Aβ oligomers, and marked down-regulation of several synaptic proteins. Aβ12-28P treatment significantly reduced intraneuronal Aβ accumulation, including Aβ oligomer level, and inhibited loss of synaptic proteins. Furthermore, we showed significantly reduced intraneuronal Aβ accumulation in APPSW/PS1dE9/apoE KO mice compared with APPSW/PS1dE9/apoE targeted replacement mice that expressed various human apoE isoforms. Data from our co-culture and in vivo experiments indicate an essential role of apoE in the mechanism of intraneuronal Aβ accumulation and provide evidence that apoE/Aβ binding antagonists can effectively prevent this process.
  American Journal Of Pathology 03/2013; · 4.89 Impact Factor
• Article: Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis.

  Jungsu Kim, Adam E M Eltorai, Hong Jiang, Fan Liao, Philip B Verghese, Jaekwang Kim, Floy R Stewart, Jacob M Basak, David M Holtzman
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  ABSTRACT: The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for Alzheimer's disease (AD). The influence of apoE on amyloid β (Aβ) accumulation may be the major mechanism by which apoE affects AD. ApoE interacts with Aβ and facilitates Aβ fibrillogenesis in vitro. In addition, apoE is one of the protein components in plaques. We hypothesized that certain anti-apoE antibodies, similar to certain anti-Aβ antibodies, may have antiamyloidogenic effects by binding to apoE in the plaques and activating microglia-mediated amyloid clearance. To test this hypothesis, we developed several monoclonal anti-apoE antibodies. Among them, we administered HJ6.3 antibody intraperitoneally to 4-mo-old male APPswe/PS1ΔE9 mice weekly for 14 wk. HJ6.3 dramatically decreased amyloid deposition by 60-80% and significantly reduced insoluble Aβ40 and Aβ42 levels. Short-term treatment with HJ6.3 resulted in strong changes in microglial responses around Aβ plaques. Collectively, these results suggest that anti-apoE immunization may represent a novel AD therapeutic strategy and that other proteins involved in Aβ binding and aggregation might also be a target for immunotherapy. Our data also have important broader implications for other amyloidosis. Immunotherapy to proteins tightly associated with misfolded proteins might open up a new treatment option for many protein misfolding diseases.
  Journal of Experimental Medicine 11/2012; · 13.85 Impact Factor
• Article: APOE4-specific changes in Aβ accumulation in a new transgenic model of Alzheimer's Disease.

  Katherine L Youmans, Leon M Tai, Evelyn Nwabuisi-Heath, Lisa Jungbauer, Takahisa Kanekiyo, Ming Gan, Jungsu Kim, William A Eimer, Steve Estus, G William Rebeck, Edwin J Weeber, Goujun Bu, Chunjiang Yu, Mary Jo Ladu
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  ABSTRACT: APOE4 is the greatest risk factor for Alzheimers disease (AD) and synergistic effects with amyloid-β peptide (Aβ) suggest interactions among apoE isoforms and different forms of Aβ accumulation. However, it remains unclear how APOE genotype affects plaque morphology, intraneuronal Aβ, soluble Aβ42, and oligomeric Aβ (oAβ), particularly in vivo. As introduction of human APOE significantly delays amyloid deposition in transgenic mice expressing familial-AD (FAD) mutations (FAD-Tg), 5xFAD-Tg mice, which exhibit amyloid deposition by 2-months, were crossed with apoE targeted-replacement mice to produce the new EFAD-Tg mice. Compared to 5xFAD mice, Aβ deposition was delayed ~4 months in the EFAD mice, allowing detection of early changes in Aβ accumulation from 2-6 months. While plaque deposition is generally greater in E4FAD mice, E2/E3FAD have significantly more diffuse and E4FAD more compact plaques. As a first report in FAD-Tg mice, APOE genotype had no effect on intraneuronal Aβ accumulation in EFAD mice. In E4FAD mice, total apoE levels were lower and total Aβ levels higher than E2FAD and E3FAD mice. Profiles from sequential three-step extractions (TBS, detergent and formic acid) demonstrate that the lower level of total apoE4 is reflected only in the detergent-soluble fraction, indicating that less apoE4 is lipoprotein-associated, and perhaps less lipidated, compared with apoE2 and apoE3. Soluble Aβ42 and oAβ levels were highest in E4FAD mice, although soluble apoE2, apoE3 and apoE4 levels were comparable, suggesting that the differences in soluble Aβ42 and oAβ result from functional differences among the apoE isoforms. Thus, APOE differentially regulates multiple aspects of Aβ accumulation.
  Journal of Biological Chemistry 10/2012; · 4.77 Impact Factor
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  Available from: Raymond Scott Turner

  Article: Mercaptoacetamide-based class II HDAC inhibitor lowers Aβ levels and improves learning and memory in a mouse model of Alzheimer's disease.

  You Me Sung, Taehee Lee, Hyejin Yoon, Amanda Marie Dibattista, Jungmin Song, Yoojin Sohn, Emily Isabella Moffat, R Scott Turner, Mira Jung, Jungsu Kim, Hyang-Sook Hoe
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  ABSTRACT: Histone deacetylase inhibitors (HDACIs) alter gene expression epigenetically by interfering with the normal functions of HDAC. Given their ability to decrease Aβ levels, HDACIs are a potential treatment for Alzheimer's disease (AD). However, it is unclear how HDACIs alter Aβ levels. We developed two novel HDAC inhibitors with improved pharmacological properties, such as a longer half-life and greater penetration of the blood-brain barrier: mercaptoacetamide-based class II HDACI (coded as W2) and hydroxamide-based class I and IIHDACI (coded as I2) and investigated how they affect Aβ levels and cognition. HDACI W2 decreased Aβ40 and Aβ42 in vitro. HDACI I2 also decreased Aβ40, but not Aβ42. We systematically examined the molecular mechanisms by which HDACIs W2 and I2 can decrease Aβ levels. HDACI W2 decreased gene expression of γ-secretase components and increased the Aβ degradation enzyme Mmp2. Similarly, HDACI I2 decreased expression of β- and γ-secretase components and increased mRNA levels of Aβ degradation enzymes. HDACI W2 also significantly decreased Aβ levels and rescued learning and memory deficits in aged hAPP 3xTg AD mice. Furthermore, we found that the novel HDACI W2 decreased tau phosphorylation at Thr181, an effect previously unknown for HDACIs. Collectively, these data suggest that class II HDACls may serve as a novel therapeutic strategy for AD.
  Experimental Neurology 10/2012; · 4.70 Impact Factor