Your search for: 'author:("Buxbaum, Joseph D.")' has returned 4 results. (0.008s) Save search

Authors: Buxbaum, Joseph D. | Geoghagen, Neil S.M. | Friedhoff, Lawrence T.

Article Type: Research Article

Abstract: Epidemiological studies have demonstrated that hypercholsterolemia is a significant risk factor for Alzheimer's disease (AD). The mechanism by which increased cholesterol may contribute to AD is unknown. However, as the generation and accumulation of the amyloid Aβ peptide in the brain appears to be significant for the initiation and progression of AD, it is possible that cholesterol levels can regulate Aβ formation and/or clearance. To test the effects of altering cholesterol on Aβ formation, we incubated cells in the presence of lipid depleted serum, with or without the active metabolite of the HMG-CoA reductase inhibitor lovastatin. After confirming that cholesterol …was depleted in the cells, we then measured the fraction of Aβ formed from its precursor βPP under each condition. We observed that cholesterol depletion led to a profound decrease in the levels of Aβ released from the cells. This effect of lovastatin acid was observed at concentrations of 0.05–5 μM, ranges where this compound is effective at inhibiting HMG-CoA reductase, thereby inhibiting cholesterol synthesis. In contrast, the release of an additional AβPP fragment, AβPPs, was only modestly reduced by cholesterol treatment. In further studies, we determined that the decreased release of Aβ was not due to its accumulation in the cell, but rather due to decreased formation of Aβ. Finally, we were able to exclude decreased maturation (glycosylation and sulfation) of newly synthesized AβPP as a cause for the effects of lovastatin acid on βPP processing and Aβ formation. Our results demonstrate that reducing cellular cholesterol by the use of an HMG-CoA reductase inhibitor regulates Aβ formation. This effect may involve alterations in the trafficking of AβPP and/or alterations in the activity of the proteases that cleave AβPP. The results suggest a mechanism by which hypercholesterolemia may increase risk for AD and indicate that reduction in cholesterol may delay the onset and/or slow the progression of AD. Show more

DOI: 10.3233/JAD-2001-3207

Citation: Journal of Alzheimer's Disease, vol. 3, no. 2, pp. 221-229, 2001

Authors: Sharman, Matthew J. | Morici, Michael | Hone, Eugene | Berger, Tamar | Taddei, Kevin | Martins, Ian J. | Lim, Wei Ling F. | Singh, Sajla | Wenk, Markus R. | Ghiso, Jorge | Buxbaum, Joseph D. | Gandy, Sam | Martins, Ralph N.

Article Type: Research Article

Abstract: The ε4 allele of apolipoprotein E (APOE) is currently the major genetic risk factor identified for Alzheimer's disease (AD). Previous in vivo data from our laboratory has demonstrated that amyloid-β (Aβ) is rapidly removed from the plasma by the liver and kidney and that the rate of its clearance is affected by ApoE in C57BL/6J and APOE-/- mice. To expand upon these findings, we assessed the peripheral clearance of human synthetic Aβ42 in APOE ε2, ε3, and ε4 knock-in and APOE knock-out mice injected with lipidated recombinant apoE2, E3, and E4 protein. Our results show that APOE does influence the …rate at which the mice are able to clear Aβ42 from their bloodstream. Both APOE ε4 mice and APOE knock-out mice treated with lipidated recombinant apoE4 demonstrated increased retention of plasma Aβ42 over time compared to APOE ε2/APOE knock-out rE2 and APOE ε3/APOE knock-out rE3 mice. These findings suggest that the peripheral clearance of Aβ42 is significantly altered by APOE genotype. Given that APOE ε4 is a risk factor for AD, then these novel findings provide some insight into the role of ApoE isoforms on the peripheral clearance of Aβ which may impact on clearance from the brain. Show more

Keywords: Alzheimer's disease, amyloid-β, APOE genotype, peripheral sink hypothesis

DOI: 10.3233/JAD-2010-100141

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 403-409, 2010

Authors: Sharman, Matthew J. | Shui, Guanghou | Fernandis, Aaron Z. | Lim, Wei Ling F. | Berger, Tamar | Hone, Eugene | Taddei, Kevin | Martins, Ian J. | Ghiso, Jorge | Buxbaum, Joseph D. | Gandy, Sam | Wenk, Markus R. | Martins, Ralph N.

Article Type: Research Article

Abstract: It is known that apolipoprotein E (ApoE) is essential for normal lipid metabolism. ApoE is the major apolipoprotein in the central nervous system and plays a key role in neurobiology by mediating the transport of cholesterol, phospholipids, and sulfatides. We therefore examined APOE ε2, ε3, and ε4 knock-in mice, using electrospray ionization mass spectrometry to determine if APOE genotype or age leads to altered levels in the brain of a number of glycerophospholipids (phosphatidylinositol, PI; phosphatidylethanolamine, PE; phosphatidic acid, PA, phosphatidylserine, PS; phosphatidylcholine, PC), sphingolipids (sphingomyelin, SM; ceramide, Cer), cholesterol, and triacylglycerols. We observed slight changes within individual PI, PE, …PC, Cer, and SM lipid levels in APOE ε2 and ε4 mice compared to APOE ε3 mice. However, overall, we did not observe any major effects in APOE ε4 knock-in mice for the levels of the glycerophospholipids measured, as compared to APOE ε2 and ε3 mice. Our findings indicate that variations in ApoE isoforms do not per se affect bulk lipid homeostasis in the brain. These findings indicate that APOE ε4 is not associated with disturbances in brain sterol or sphingolipids in the absence of environmental factors. Show more

Keywords: Alzheimer's disease, APOE genotype, cholesterol, glycerophospholipids, lipidomics, sphingolipids

DOI: 10.3233/JAD-2010-1348

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 105-111, 2010

Authors: Sarapas, Casey | Cai, Guiqing | Bierer, Linda M. | Golier, Julia A. | Galea, Sandro | Ising, Marcus | Rein, Theo | Schmeidler, James | Müller-Myhsok, Bertram | Uhr, Manfred | Holsboer, Florian | Buxbaum, Joseph D. | Yehuda, Rachel

Article Type: Research Article

Abstract: We have previously reported the differential expression of 17 probe sets in survivors of the 9/11 attacks with current posttraumatic stress disorder (PTSD) compared to similarly exposed survivors with no lifetime PTSD. The current study presents an expanded analysis of these subjects, including genotype at FKBP5, a modulator of glucocorticoid receptor (GR) sensitivity. It includes data from additional subjects who developed PTSD following 9/11 but then recovered, distinguishing expression profiles associated with risk for developing PTSD, resilience, and symptom recovery. 40 Caucasians (20 with and 20 without PTSD, matched for exposure, age, and gender) were selected from a population-representative sample …of persons exposed to the 9/11 attacks from which longitudinal data had been collected in four previous waves. Whole blood gene expression and cortisol levels were obtained and genome-wide gene expression was analyzed. 25 probe sets were differentially expressed in PTSD. Identified genes were generally involved in hypothalamic-pituitary-adrenal axis, signal transduction, or in brain and immune cell function. STAT5B, a direct inhibitor of GR, and nuclear factor I/A, both showed reduced expression in PTSD. Comparison of lifetime versus current PTSD identified overlapping genes with altered expression suggesting enduring markers, while some markers present only in current PTSD may reflect state measures. As a follow-up, direct comparisons of expression in current PTSD, lifetime-only PTSD, and control groups identified FKBP5 and MHC Class II as state markers, and also identified several trait markers. An analysis of indirect effects revealed that homozygosity for any of 4 PTSD risk-related polymorphisms at FKBP5 predicted FKBP5 expression, which mediated indirect effects of genotype on plasma cortisol and PTSD severity. Show more

Keywords: Stress disorders, post-traumatic, gene expression, genotype, FKBP5 protein, human, cortisol, September 11 terrorist attacks, childhood trauma

DOI: 10.3233/DMA-2011-0764

Citation: Disease Markers, vol. 30, no. 2-3, pp. 101-110, 2011