Alzheimer Disease: Kim D

Kim D, Tsai LH. · Howard Hughes Medical Institute, MIT Picower Institute for Learning and Memory, Cambridge, MA 02139, USA. · Cell. · Pubmed #19524503 No free full text.

Abstract: The APP-processing pathway is a pathological component of Alzheimer's disease (AD), but there is no consensus regarding the physiological functions of APP and its products. Two studies (Nikolaev et al., 2009; Lauren et al., 2009) link the physiological and pathological aspects of APP processing. They show that the APP products, N-APP and Abeta42, are ligands for death receptor 6 and cellular prion protein, respectively, which are important in nervous system development and synaptic suppression.

Ahn SM, Byun K, Cho K, Kim JY, Yoo JS, Kim D, Paek SH, Kim SU, Simpson RJ, Lee B. · Center for Genomics and Proteomics, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Korea. · PLoS One. · Pubmed #18665237 links to  free full text

Abstract: Albumin, an abundant plasma protein with multifunctional properties, is mainly synthesized in the liver. Albumin has been implicated in Alzheimer's disease (AD) since it can bind to and transport amyloid beta (Abeta), the causative agent of AD; albumin is also a potent inhibitor of Abeta polymerization. Despite evidence of non-hepatic transcription of albumin in many tissues including kidney and pancreas, non-hepatic synthesis of albumin at the protein level has been rarely confirmed. In a pilot phase study of Human Brain Proteome Project, we found evidence that microglial cells in brain may synthesize albumin. Here we report, for the first time, the de novo synthesis of albumin in human microglial cells in brain. Furthermore, we demonstrate that the synthesis and secretion of albumin from microglial cells is enhanced upon microglial activation by Abeta(1-42)- or lipopolysaccharide (LPS)-treatment. These data indicate that microglial cells may play a beneficial role in AD by secreting albumin that not only inhibits Abeta polymerization but also increases its clearance.

Yoon S, Choi J, Haam J, Choe H, Kim D. · Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Korea. · Neuroreport. · Pubmed #18007179 No free full text.

Abstract: Treatment of neurons with okadaic acid, a protein phosphatase-2A inhibitor, has been used to induce tau phosphorylation and neuronal death, and to create a research model of Alzheimer's disease. Amyloid precursor protein (APP) is the precursor protein of the beta-amyloid peptide that accumulates in extracellular plaques in Alzheimer's disease. Several studies have shown that mint-1 (munc18-interacting protein 1) and mint-2 bind to the YENPTY motif in the cytoplasmic domain of APP and inhibit processing of APP to beta-amyloid peptide. Here, we report that, upon neurodegeneration with okadaic acid, mint-1 and mint-2 levels were reduced by proteolytic cleavage, and that these changes were followed by increases in APP levels. We also show that the mint-1 and mint-2 cleavage and APP overexpression were prevented by calpain inhibitor-I and inhibitor-II. These results indicate that mint cleavage might play a role in the pathophysiology of Alzheimer's disease.

Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT, Delalle I, Baur JA, Sui G, Armour SM, Puigserver P, Sinclair DA, Tsai LH. · Howard Hughes Medical Institute, Picower Insitute for Learning and Memory, Riken-MIT Neuroscience Research Center, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Boston, MA, USA. · EMBO J. · Pubmed #17581637 links to  free full text

Abstract: A progressive loss of neurons with age underlies a variety of debilitating neurological disorders, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), yet few effective treatments are currently available. The SIR2 gene promotes longevity in a variety of organisms and may underlie the health benefits of caloric restriction, a diet that delays aging and neurodegeneration in mammals. Here, we report that a human homologue of SIR2, SIRT1, is upregulated in mouse models for AD, ALS and in primary neurons challenged with neurotoxic insults. In cell-based models for AD/tauopathies and ALS, SIRT1 and resveratrol, a SIRT1-activating molecule, both promote neuronal survival. In the inducible p25 transgenic mouse, a model of AD and tauopathies, resveratrol reduced neurodegeneration in the hippocampus, prevented learning impairment, and decreased the acetylation of the known SIRT1 substrates PGC-1alpha and p53. Furthermore, injection of SIRT1 lentivirus in the hippocampus of p25 transgenic mice conferred significant protection against neurodegeneration. Thus, SIRT1 constitutes a unique molecular link between aging and human neurodegenerative disorders and provides a promising avenue for therapeutic intervention.

Kim H, Kim S, Go H, Kim D. · Department of Physics, Korea Advanced Institute of Science and Technology, Yusong-Gu, Taejon. · Biol Cybern. · Pubmed #11471836 No free full text.

Abstract: A spatio-temporal analysis has been employed on EEG signals recorded in groups of patients with Alzheimer's disease (AD). The so-called Karhunen-Loeve analysis method was applied to four groups of subjects: 12 patients who were diagnosed as having severe AD, 8 mild AD patients, 10 vascular dementia patients, and 10 normal aged controls, to obtain the spatio-temporal eigenpatterns. The local difference of the global EEG pattern in mild AD patients from that of normal controls was expanded to the frontal regions in the case of severe AD. The analysis showed significant bilateral temporal functioning differences and inter-hemispheric connection difficulty, along with remarkable intra-hemispheric correlation in severe AD patients. Compared to the normal controls, severe AD patients' brains exhibit only weak local connections and correlations, resulting into limited harmonious inter-hemispheric information processing. The results from the spatio-temporal EEG study of AD patients can be considered to be due to a change in the relative activity of the brain corresponding to the pathologic variation in AD, and the results are in accordance with reported clinical studies.