Biomedical subjects

Hyoung-gon Lee

Publications and source records attributed to Hyoung-gon Lee.

24 records · Page 2Linked to original sources

PubMed2004

Perspectives on the amyloid-beta cascade hypothesis.

For the better part of the past two decades, studies on the molecular, biochemical and cellular mechanisms of Alzheimer disease have focused on amyloid-beta protein, the major proteinaceous component of senile plaques. In fact, the Amyloid Cascade Hypothesis has come to dominate the field both in terms of proposed disease mechanism as well as potential for therapeutic intervention. In this review, we look at the Amyloid Cascade Hypothesis from the perspective of pathology, cell biology, and genetics. In all cases, alternate interpretations of old data as well as new evidence indicates that amyloid-beta, far from being the harbinger of disease, actually occurs secondary to more fundamental pathological changes and may even play a protective role in the diseased brain. These findings bring into serious doubt the validity of the Amyloid Cascade Hypothesis as the central cause of Alzheimer disease and, consequently, the potential usefulness of therapeutic targets against amyloid-beta.

Aged↗

PubMed2003

Distribution, levels, and activation of MEK1 in Alzheimer's disease.

Extracellular-signal-regulated kinase (ERK) has been implicated in the pathogenesis of Alzheimer's disease (AD), but the upstream cascade leading to ERK activation has not been elucidated. In this study, we focused on one of the physiological activators of ERK, mitogen-activated protein kinase (MAPK)/ERK kinase 1 (MEK1). Although there was no significant difference in the level and distribution of total MEK1 between AD and age-matched control cases, increased levels of activated phospho-MEK1 were specifically localized to neuronal intracytoplasmic granular structures in severe AD (Braak stage V-VI). The considerable overlap between MEK1 and its downstream effector, phospho-ERK, suggests both a functional and mechanistic link. Nuclear localization of phospho-MEK1 was a prominent feature in both mild AD cases (Braak stage III-IV) and control cases with limited pathology (Braak stage I-II). Since MEK1 is normally cytoplasmic due to the active export from nucleus because of the presence of nuclear export signal in its amino-terminus, we suspect that the apparent nuclear accumulation of phospho-MEK1 in AD patients at early stages suggests that abnormal nuclear trafficking may contribute to the pathogenesis of AD. By immunoblot analyses, phospho-MEK1 was significantly increased in AD over control cases. Together, these findings lend further credence to the notion that the ERK pathway is dysregulated in AD and also indicate an active role for this pathway in disease pathogenesis.

Active Transport, Cell Nucleus↗

PubMed2003

Increased p27, an essential component of cell cycle control, in Alzheimer's disease.

A number of recent findings have demonstrated re-expression of cell cycle-related proteins in vulnerable neurones in Alzheimer's disease. We hypothesize that this attempt by neurones to re-enter mitosis is a response to external growth stimuli that leads to an abortive re-entry into the cell cycle and, ultimately, neuronal degeneration. In this study, to further delineate the role of mitotic processes in the pathogenesis of Alzheimer's disease, we investigated p27, a cyclin-dependent kinase inhibitor that plays a negatively regulatory role in cell cycle progression that, once phosphorylated at Thr187, is degraded via an ubiquitin-proteasome pathway. Here we report that both p27 and phosphorylated p27 (Thr187) show increases in the cytoplasm of vulnerable neuronal populations in Alzheimer's disease vs. age-matched control subjects. Importantly, phosphorylated p27 (Thr187) shows considerable overlap with tau-positive neurofibrillary pathology, including neurofibrillary tangles, dystrophic neurites and neuropil threads. The findings presented here suggest that dysregulation of the cell cycle plays a crucial role in the pathogenesis of Alzheimer's disease that may provide a novel mechanistic basis for therapeutic intervention.

Aged↗

PubMed2003

Will preventing protein aggregates live up to its promise as prophylaxis against neurodegenerative diseases?

Protein aggregation and misfolding characterize most age-related neurodegenerative diseases including Alzheimer, Parkinson and Huntington diseases. Protein aggregation has generally been assumed to be responsible for neurodegeneration in these disorders due to association and genetics. However, protein aggregation may, in fact, be an attempt to protect neurons from the stress resulting from the disease etiology. In this review, we weigh the evidence of whether removal of amyloids, aggregates and neuronal inclusions represent a reasonable strategy for protecting neurons.

Amyloid↗

PubMedDate not supplied

The role of mitogen-activated protein kinase pathways in Alzheimer's disease.

Given the critical role of mitogen-activated protein kinase (MAPK) pathways in regulating cellular processes that are affected in Alzheimer's disease (AD), the importance of MAPKs in disease pathogenesis is being increasingly recognized. All MAPK pathways, i.e., the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 pathways, are activated in vulnerable neurons in patients with AD suggesting that MAPK pathways are involved in the pathophysiology and pathogenesis of AD. Here we review recent findings implicating the MAPK pathways in AD and discuss the relationship between these pathways and the prominent pathological processes, i.e., tau phosphorylation and amyloid-beta deposition, as well as the functional association to amyloid beta protein precursor. We suggest that regulation of these pathways may be a central facet to any potential treatment for the disease.

Alzheimer Disease↗

PubMedDate not supplied

Differential regulation of glutamate receptors in Alzheimer's disease.

Selective neurodegeneration is a prominent feature in Alzheimer's disease; however, the mechanism of neuronal death is still unclear. Nonetheless, the topographical distribution of different types of receptors is thought to contribute to the regional selective nature of neuronal degeneration. Specifically, since glutamatergic transmission is severely altered by the early degeneration of cortico-cortical connections and hippocampal projections in Alzheimer's disease, we suspect that glutamate receptors may play a new role in the pathophysiology of disease. Here we review the salient aspects of glutamate receptor expression in Alzheimer's disease and how their differential regulation can contribute to the selective neurodegeneration seen in the disease. Additionally, we assess the potential therapeutic value of glutamate receptors as a target for drug intervention in Alzheimer's disease.

Alzheimer Disease↗