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Hyoung-gon Lee

Publications and source records attributed to Hyoung-gon Lee.

At least 19 recordsLinked to original sources
PubMed2007

Amyloid-beta in Alzheimer disease: the null versus the alternate hypotheses.

For nearly 20 years, the primary focus for researchers studying Alzheimer disease has been centered on amyloid-beta, such that the amyloid cascade hypothesis has become the "null hypothesis." Indeed, amyloid-beta is, by the current definition of the disease, an obligate player in pathophysiology, is toxic to neurons in vitro, and, perhaps most compelling, is increased by all of the human genetic influences on the disease. Therefore, targeting amyloid-beta is the focus of considerable basic and therapeutic interest. However, an increasingly vocal group of investigators are arriving at an "alternate hypothesis" stating that amyloid-beta, while certainly involved in the disease, is not an initiating event but rather is secondary to other pathogenic events. Furthermore and perhaps most contrary to current thinking, the alternate hypothesis proposes that the role of amyloid-beta is not as a harbinger of death but rather a protective response to neuronal insult. To determine which hypothesis relates best to Alzheimer disease requires a broader view of disease pathogenesis and is discussed herein.

Alzheimer Disease↗
PubMed2006

Alzheimer disease, the two-hit hypothesis: an update.

Given the relative modality of single-insult models to accurately reflect Alzheimer disease pathogenesis, based on studies on mitogenic and oxidative stress signaling pathways, we proposed a two-hit hypothesis 2 years ago stating that both oxidative stress and mitogenic dysregulation are necessary and sufficient to cause the disease and suggested that it may be a common mechanism for other neurodegenerative diseases as well (X. Zhu, A.K. Raina, G. Perry, M.A. Smith, Alzheimer's disease: the two-hit hypothesis, Lancet Neurol. 3 (2004) 219-226). Recent developments in the field confirm some important predictions of the hypothesis and shed new lights on potential mechanisms regarding how steady state may be achieved in sporadic AD cases and therefore, in our opinion, strengthen the hypothesis, which will be the focus of this review.

Alzheimer Disease↗
PubMed2006

Aberrant localization of importin alpha1 in hippocampal neurons in Alzheimer disease.

Since many nuclear proteins are ectopically localized in the cytoplasm in the vulnerable neurons in Alzheimer disease (AD), we speculated that there is failure of the cytoplasmic-nuclear transport machinery in AD. In support of this notion, we found that importin alpha1, an essential component of cytoplasmic-nuclear transport, is abnormally accumulated in Hirano bodies in vulnerable hippocampal neurons in AD. These data suggest a hindrance in importin-mediated cytoplasmic-nuclear transport in AD.

Actins↗
PubMed2006

Neuronal cell cycle re-entry mediates Alzheimer disease-type changes.

Evidence showing the ectopic re-expression of cell cycle-related proteins in specific vulnerable neuronal populations in Alzheimer disease led us to formulate the hypothesis that neurodegeneration, like cancer, is a disease of inappropriate cell cycle control. To test this notion, we used adenoviral-mediated expression of c-myc and ras oncogenes to drive postmitotic primary cortical neurons into the cell cycle. Cell cycle re-entry in neurons was associated with increased DNA content, as determined using BrdU and DAPI, and the re-expression of cyclin B1, a marker for the G2/M phase of the cell cycle. Importantly, we also found that cell cycle re-entry in primary neurons leads to tau phosphorylation and conformational changes similar to that seen in Alzheimer disease. This study establishes that the cell cycle can be instigated in normally quiescent neuronal cells and results in a phenotype that shares features of degenerative neurons in Alzheimer disease. As such, our neuronal cell model may be extremely valuable for the development of novel therapeutic strategies.

Alzheimer Disease↗
PubMed2006

Ectopic expression of phospho-Smad2 in Alzheimer's disease: uncoupling of the transforming growth factor-beta pathway?

Transforming growth factor-beta (TGF-beta), a multifunctional cytokine, has been widely suggested to play a role in the pathogenesis of Alzheimer's disease. Supporting this, levels of TGF-beta are elevated in the cerebrospinal fluid, sera, and brain of patients with Alzheimer's disease. Since TGF-beta is neuroprotective, whereas Alzheimer's disease is typified by neurodegeneration, we speculated that defects in TGF-beta signaling might abrogate its neuroprotective properties. Consistently with an increase in TGF-beta in Alzheimer's disease, we found significant increases in phospho-Smad2, a major downstream signaling molecule of TGF-beta, in hippocampal neurons of Alzheimer's disease compared with age-matched control patients. However, in contrast to an expected nuclear localization, phosphorylated Smad2 in Alzheimer's disease was predominantly, and ectopically, found in the neuronal cytoplasm, specifically colocalized with neurofibrillary tangles and granulovacuolar degeneration. Given that a nuclear localization is required to regulate the transcription of TGF-beta target genes to afford neuroprotection, the ectopic localization of phosphorylated Smad2 suggests a defect in the Smad-mediated signaling pathway of TGF-beta in Alzheimer's disease and consequent loss of neuroprotective function.

Aged↗
PubMed2006

Amyloid beta: the alternate hypothesis.

Alzheimer disease (AD) is a devastating condition and patients, caregivers, clinicians, and scientists are eager to decipher the underlying disease mechanism and, thereafter, target this therapeutically. Most investigators studying the underlying cause of AD have focused on amyloid-beta (Abeta) such that the Amyloid Cascade Hypothesis is the predominant mechanism thought to be responsible for the disease. However, a number of caveats have led us to seriously question the validity of this hypothesis. First, in addition to increases in Abeta, genetic mutations in AD lead to increased vulnerability to oxidative/apoptotic insults indicating that the mutated protein disturbs redox balance. Whether mutations result in Abeta deposition that then causes oxidative stress or whether mutations cause oxidative stress that results in Abeta deposition is unclear. Indeed, while in vitro experiments show that Abeta can directly cause oxidative stress to cells in culture, it is apparent from other studies that the reverse is also true, namely that oxidative stress leads to increases in Abeta. Notably, in vivo studies in both sporadic and genetic forms of the disease show that oxidative stress temporally precedes increases in Abeta and that increases in Abeta are associated with a decrease in oxidative stress. Based on these findings, we herein propose an Alternate Amyloid Hypothesis in which pathogenic factors for disease lead to increased oxidative stress that then leads to increases in Abeta. Further, we propose that Abeta serves as a redox sensor and that oxidatively-induced Abeta serves to attenuate oxidative stress. Obviously, whether Abeta is the culprit, as argued by the Amyloid Cascade Hypothesis, or a much maligned protector, as argued by the Alternate Amyloid Hypothesis, is clearly important to decipher to advance our understanding and design efficacious therapeutics for this disease.

Alzheimer Disease↗
PubMed2005

Redox metals and oxidative abnormalities in human prion diseases.

Prion diseases are characterized by the accumulation of diffuse and aggregated plaques of protease-resistant prion protein (PrP) in the brains of affected individuals and animals. Whereas prion diseases in animals appear to be almost exclusively transmitted by infection, human prion diseases most often occur sporadically and, to a lesser extent, by inheritance or infection. In the sporadic cases (sporadic Creutzfeld-Jakob disease, sCJD), PrP-containing plaques are infrequent, whereas in transmitted (variant CJD) and inherited (Gerstmann-Straussler-Scheinker Syndrome) cases, plaques are a usual feature. In the current study, representative cases from each of the classes of human prion disease were analyzed for the presence of markers of oxidative damage that have been found in other neurodegenerative diseases. Interestingly, we found that the pattern of deposition of PrP, amyloid-beta, and redox active metals was distinct for the various prion diseases. Whereas 8-hydroxyguanosine has been shown to be increased in sCJD, and inducible NOS is increased in scrapie-infected mice, well-studied markers of oxidative damage that accumulate in the lesions of other neurodegenerative diseases (such as Alzheimer's disease, progressive supranuclear palsy, and Parkinson's disease), such as heme oxygenase-1 and lipid peroxidation, were not found around PrP deposits or in vulnerable neurons. These findings suggest an important distinction in prion-related oxidative stress, indicating that different neurodegenerative pathways are involved in different prion diseases.

Adult↗
PubMed2005

Mitogen- and stress-activated protein kinase 1: convergence of the ERK and p38 pathways in Alzheimer's disease.

Two of the earliest manifestations of the selective neurodegeneration that occurs in Alzheimer's disease (AD) involve the oxidative modification of various biomacromolecules and the reexpression of a multitude of cell cycle-related proteins. Taken together with the proximal and ectopic increases in activated components of the ERK and p38 pathways, involved in mitotic and cellular stress signaling, respectively, there is a clear and important role for mitotic and oxidative insults in the pathogenesis of AD. Despite the mounting evidence, however, for the causal role of mitogenic abnormalities and oxidative stress in AD pathogenesis, the effect of the converging relevant pathways due to chronic stimulation in AD remains largely unknown. To delineate further the mechanism by which mitogenic and stress signaling cascades converge, we focused on one of the downstream effectors of activated ERK and p38, mitogen- and stress-activated kinase 1 (MSK1). Activated MSK1, phosphorylated at residues Ser376 and Thr581, was upregulated in vulnerable neurons in AD when compared to that in age-matched controls, whereas MSK1 phosphorylated at residue Ser360 was not increased in AD. Furthermore, activated MSK1 phosphorylated at Thr581 colocalized strongly with activated p38 but only weakly with activated ERK, whereas MSK1 phosphorylated at Ser376 colocalized strongly with activated ERK but only weakly with activated p38, suggesting potential preferential phosphorylation sites for the two upstream effectors.

Aged↗
PubMed2005

Tau modifiers as therapeutic targets for Alzheimer's disease.

Fibrillogenesis is a major feature of Alzheimer's disease (AD) and other neurodegenerative diseases. Fibers are correlated with disease severity and they have been implicated as playing a direct role in disease pathophysiology. In studies of tau, instead of finding causality with tau fibrils, we found that tau is associated with reduction of oxidative stress. Biochemical findings show that tau oxidative modifications are regulated by phosphorylation and that tau found in neurofibrillary tangles is oxidatively modified, suggesting that tau is closely linked to the biology, not toxicity, of AD.

Aldehydes↗
PubMed2005

4-Oxo-2-nonenal is both more neurotoxic and more protein reactive than 4-hydroxy-2-nonenal.

Electrophilic aldehydes, generated from oxidation of polyunsaturated fatty acyl chains under conditions of oxidative stress, bind to proteins and polynucleotides and can lead to cell death. 4-Hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE) have been shown here to be toxic to human neuroblastoma cells in culture at low micromolar concentrations. ONE is 4-5 times more neurotoxic at concentrations near the threshold of lethality. The reactions of these two aldehydes with two model proteins, ribonuclease A and beta-lactoglobulin, and their Lys epsilon-dimethylamino derivatives, have been followed spectrophotometrically. On the basis of t(1/2) measurements for the disappearance of the alpha,beta-unsaturated chromophore, ONE is 6-31 times more reactive with these proteins. The fastest reaction of ONE with proteins involves Schiff base formation at Lys epsilon-amino groups, whereas Schiff base formation is not spectroscopically apparent for HNE. Detailed kinetic studies of the initial reactions of HNE and ONE have been carried out with amino acids and amino acid surrogates. Whereas the reactions with imidazole and thiol nucleophiles involve straightforward Michael adduct formation, kinetics analyses reveal the reversibility of both the HNE Michael adduction of amines and the ONE Schiff base adduction of amines. Although ONE is more reactive than HNE toward conjugate addition of imidazole and thiol nucleophiles, it is less reactive than HNE toward Lys/amine Michael adduction. The greater neurotoxicity of ONE could reflect in part the different reactivity characteristics of ONE as compared to HNE.

Aldehydes↗
PubMed2005

Therapeutic opportunities in Alzheimer disease: one for all or all for one?

In recent years, Alzheimer disease (AD) has received great attention as an incurable and fatal disease that threatens the lives of aging individuals. Debates regarding areas of research and treatment designs have made headlines as scientists in the field question ongoing work. Despite these academic quarrels, significant insights concerning the cellular and molecular basis of AD have illuminated the potential causes and consequences of AD pathogenesis in the human brain. Additionally, assigning relationships among scientific evidence is difficult due to the nature of the disease. It is crucial to note that all findings do not constitute causality as AD has many stages of progression, and therefore a particular finding may reflect disease epiphenomenon. Determining the primary causes of disease are even more problematic when considering that a succinct timeline in which a normal aging brain develops AD-like changes due to a single cause may not be appropriate, as increasing lines of evidence indicate that multiple factors likely contribute to the clinical manifestation of AD. Implications for therapeutic strategies are dramatically affected by viewing AD as a multi-factorial disease state, one specific treatment may not be able to prevent or reverse AD if this is indeed the case. In this regard, the current focus on individual therapeutic targets may prove to be ineffective in the successful treatment of AD; however, if taken in combination, these singular therapies may likely result in the global suppression of AD. In this review, the scientific basis for common AD therapeutics as well as the efficacy of these treatments will be discussed.

Alzheimer Disease↗
PubMed2004

Aberrant expression of metabotropic glutamate receptor 2 in the vulnerable neurons of Alzheimer's disease.

Selective neuronal dysfunction and degeneration are defining features of Alzheimer's disease (AD). While the exact mechanism(s) contributing to this selective neuronal vulnerability remains to be elucidated, we hypothesized that the differential expression of metabotropic glutamate receptors (mGluRs) may play a key role in this process since the various mGluR groups differentially regulate neuronal cell death and survival. In the present study, we focused on the metabotropic glutamate receptor 2 (mGluR2), a subtype of group II mGluRs. The mGluR2 is expressed at low levels in pyramidal neurons in age-matched control cases, whereas we found a strikingly increased mGluR2 expression in AD, in a pattern that mirrored both the regional and cellular subtype of neuronal vulnerability to degeneration and neurofibrillary alterations. Immunoblot analysis confirmed the significant increase in the level of mGluR2 in AD compared with age-matched controls. Agonists for group II mGluRs activate extracellular receptor kinase (ERK), a kinase that is chronically activated in vulnerable neurons of AD. ERK is able to phosphorylate tau protein, so the up-regulation of mGluR2 in vulnerable neurons may represent the upstream mediator of abnormal tau phosphorylation in AD. Immunocytochemical examination revealed considerable overlap between mGluR2 and neurofibrillary alterations. Thus, it is likely that mGluR2 represents a novel therapeutic target for AD.

Aged↗
PubMed2004

Neuroprotective properties of Bcl-w in Alzheimer disease.

While there is a host of pro-apoptotic stimuli that target neurons in Alzheimer disease (AD), given the chronicity of the disease and the survival of many neurons, those neurons must either avoid or, at minimum, delay apoptotic death signaling. In this study, we investigated Bcl-w, a novel member of the Bcl-2 family that promotes cell survival. In AD, we found increased levels of Bcl-w associated with neurofibrillary pathology and punctate intracytoplasmic structures whereas, in marked contrast, there are only low diffuse levels of Bcl-w in the neuronal cytoplasm of age-matched control cases. Immunoblot analysis confirmed that Bcl-w levels were significantly increased in AD. By electron microscopy, we determined that the increased Bcl-w expression in AD was ultrastructurally localized to mitochondria and neurofibrillary pathology. To investigate the cause and consequence of Bcl-w up-regulation in neurons, we found that fibrillized amyloid-beta led to increased Bcl-w protein levels in M17 human neuroblastoma cells, and that overexpression of Bcl-w significantly protected neurons against staurosporine- and amyloid-beta-induced apoptosis. Taken together, these series of results suggest that Bcl-w may play an important protective role in neurons in the diseased brain and that this aspect could be therapeutically harnessed to afford neuroprotection.

Adolescent↗