Mercury induced the Accumulation of Amyloid Beta (Abeta) in PC12 Cells: The Role of Production and Degradation of Abeta

Extracellular accumulation of amyloid beta protein (Abeta) plays a central role in Alzheimer's disease (AD). Some metals, such as copper, lead, and aluminum can affect the Abeta accumulation in the brain. However, the effect of mercury on Abeta accumulation in the brain is not clear. Thus, this study was proposed to estimate whether mercury concentration affects Abeta accumulation in PC12 cells. We treated 10, 100, and 1000 nM HgCl2 (Hg) or CH3HgCl2 (MeHg) for 48 hr in PC12 cells. After treatment, Abeta40 in culture medium increased in a dose- and time-dependent manner. Hg and MeHg increased amyloid precursor protein (APP), which is related to Abeta production. Neprilysin (NEP) levels in PC12 cells were decreased by Hg and MeHg treatment. These results suggested that Hg induced Abeta accumulation through APP overproduction and reduction of NEP.

Screening and Optimal Extraction of a New Antidementia beta-Secretase Inhibitor-Containing Mushroom

To produce a potent antidementia beta-secretase inhibitor from a mushroom, the beta-secretase inhibitory activities of various mushroom extracts were determined. Methanol extracts of Lentinula edodes exhibited the highest inhibitory activity (40.1%). The inhibitor was maximally extracted when a fruiting body of L. edodes was treated with 50% methanol at 40degrees C for 24 h.

Non-Steroidal Anti-Inflammatory Drugs Change Various Inflammatory Mediator-Related Gene Expression In Abeta1-42 Activated Mouse Microglial Cell

BACKGROUND: We investigated whether non-steroidal anti-inflammatory drugs(NSAIDs) could influence the expression of a few inflammatory mediator-related genes in amyloid-beta1-42(Abeta42)-activated microglia. METHODS: BV-2 cells, a murine microglial cell line, were pretreated with a single dose of 20microM of aggregated Abeta42 for 18 hours followed by incubation with ibuprofen(100microM), indomethacin(150microM) or ketorolac(10nM) for 24 hours. Expression of mRNAs for CCL7(beta-chemokine), CXCL2(alpha-chemokine), CCR7(beta-chemokine receptor), interleukin(IL)-1alpha, matrix metalloproteinase(MMP)-3, beta-secretase(BACE1) and cyclooxygenase(COX)-2 gene were measured with quantitative realtime reverse transcriptase(RT)-PCR. RESULTS: Abeta42 increased expression of mRNAs for CCL7, CXCL2, CCR7, IL-1alpha, MMP-3, BACE1 and COX-2 genes. Administration of each NSAIDs effectively lowered the expression of these genes in Abeta42-activated microglia. CONCLUSION: NSAIDs inhibit increased expression of a few cytokines, chemokine receptor and inflammatory mediatorrelated protease genes in Abeta42-activated microglia. These data demonstrate a possible mechanism how NSAIDS may decrease the risk and delay the onset of chronic neuroinflammatory process in AD.

Effect of Ischemic Neuronal Insults on Amyloid Precursor Protein Processing

BACKGROUND: In spite of the different pathogenesis and exclusive respect in the diagnosis of Alzheimer's disease (AD) and vascular dementia (VaD), recent epidemiological and pathological studies indicates that ischemic stroke have an important role in the pathogenesis of both VaD and AD. However, the association of ischemic stroke and AD on the cellular and molecular level is still unknown. We evaluated the effect of ischemic neuronal insult on the regulation of amyloid precursor protein (APP) processing. METHODS: We used an in vitro model of cerebral ischemia (oxygen-glucose deprivation, OGD) to evaluate the effect of ischemic insult on the amyloidogenic and non-amyloidogenic pathways using human neuroblastoma cell line, SH-SY5Y, and primary cultured cells of Tg2576 APP transgenic mouse. RESULTS: Ischemic insult significantly increased the beta amyloid (A beta) production in the primary cultured cells of Tg2576 APP transgenic mice (p<0.001). A disintegrin and metalloprotease 10 (ADAM 10), a candidate of alpha-secretase, was markedly increased in the early stage of ischemic insult (up to 2 hours of OGD, p<0.001; 4 hours of OGD, p<0.05), which was followed by the decreased level of ADAM 10 expression in a later stage (p<0.001). However, the protein and mRNA expression of beta-site cleavage enzyme (BACE) and BACE activity were not significantly different between the group of ischemic insult and control. By contrast, the activity of gamma-secretase was significantly increased after 4 hours of ischemic insult, as compared to controls. CONCLUSIONS: This study demonstrates that the ischemic neuronal insults increase the production of A beta via activation of the amyloidogenic pathway, which may link the role of ischemic insults to the pathogenesis of AD.