Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Neurology
Published in: BMC Neurology 1/2015

Open Access 01-12-2015 | Research article

Dose-specific effect of simvastatin on hypoxia-induced HIF-1α and BACE expression in Alzheimer’s disease cybrid cells

Authors: Jin-Heon Jeong, Kyu Sun Yum, Jun Young Chang, Manho Kim, Jin-young Ahn, SangYun Kim, Paul A Lapchak, Moon-Ku Han

Published in: BMC Neurology | Issue 1/2015

Login to get access

Abstract

Background

Alzheimer’s disease (AD) is associated with vascular risk factors; brain ischemia facilitates the pathogenesis of AD. Recent studies have suggested that the reduction of AD risk with statin was achieved by decreased amyloidogenic amyloid precursor protein.

Methods

We used mitochondrial transgenic neuronal cell (cybrid) models to investigate changes in the levels of intracellular hypoxia inducible factor 1α (HIF-1α) and β-site amyloid precursor protein cleaving enzyme (BACE) in the presence of simvastatin. Sporadic AD (SAD) and age-matched control (CTL) cybrids were exposed to 2 % O2 and incubated with 1 μM or 10 μM simvastatin.

Results

There was no significant difference between cell survival by 1 or 10 μM simvastatin in both SAD and CTL cybrids. In the presence of 1 μM simvastatin, intracellular levels of HIF-1α and BACE decreased by 40–70 % in SAD, but not CTL cybrids. However, 10 μM simvastatin increased HIF-1α and BACE expression in both cybrid models.

Conclusion

Our results suggest demonstrate differential dose-dependent effects of simvastatin on HIF-1α and BACE in cultured Alzheimer’s disease cybrid cells.
Literature
1.
Braak H, Braak E. Evolution of the neuropathology of Alzheimer's disease. Acta Neurol Scand Suppl. 1996;165:3–12.CrossRefPubMed
2.
de la Torre JC. Alzheimer disease as a vascular disorder: nosological evidence. Stroke. 2002;33:1152–62.CrossRefPubMed
3.
Koistinaho M, Koistinaho J. Interactions between Alzheimer's disease and cerebral ischemia--focus on inflammation. Brain Res Brain Res Rev. 2005;48:240–50.CrossRefPubMed
4.
Sun X, He G, Qing H, Zhou W, Dobie F, Cai F, et al. Hypoxia facilitates Alzheimer's disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci U S A. 2006;103:18727–32.CrossRefPubMedPubMedCentral
5.
Zhang X, Zhou K, Wang R, Cui J, Lipton SA, Liao FF, et al. Hypoxia-inducible factor 1alpha (HIF-1alpha)-mediated hypoxia increases BACE1 expression and beta-amyloid generation. J Biol Chem. 2007;282:10873–80.CrossRefPubMed
6.
Guglielmotto M, Aragno M, Autelli R, Giliberto L, Novo E, Colombatto S, et al. The up-regulation of BACE1 mediated by hypoxia and ischemic injury: role of oxidative stress and HIF1alpha. J Neurochem. 2009;108:1045–56.CrossRefPubMed
7.
8.
Stepien K, Tomaszewski M, Czuczwar SJ. Neuroprotective properties of statins. Pharmacol Rep. 2005;57:561–9.PubMed
9.
Wang Q, Yan J, Chen X, Li J, Yang Y, Weng J, et al. Statins: multiple neuroprotective mechanisms in neurodegenerative diseases. Exp Neurol. 2011;230:27–34.CrossRefPubMed
10.
Dichtl W, Dulak J, Frick M, Alber HF, Schwarzacher SP, Ares MP, et al. HMG-CoA reductase inhibitors regulate inflammatory transcription factors in human endothelial and vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2003;23:58–63.CrossRefPubMed
11.
Ogunshola OO, Antoniou X. Contribution of hypoxia to Alzheimer's disease: is HIF-1alpha a mediator of neurodegeneration? Cell Mol Life Sci. 2009;66:3555–63.CrossRefPubMed
12.
Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet. 2000;356:1627–31.CrossRefPubMed
13.
Sidera C, Parsons R, Austen B. The regulation of beta-secretase by cholesterol and statins in Alzheimer's disease. J Neurol Sci. 2005;229–230:269–73.CrossRefPubMed
14.
Cole SL, Grudzien A, Manhart IO, Kelly BL, Oakley H, Vassar R. Statins cause intracellular accumulation of amyloid precursor protein, beta-secretase-cleaved fragments, and amyloid beta-peptide via an isoprenoid-dependent mechanism. J Biol Chem. 2005;280:18755–70.CrossRefPubMed
15.
Parsons RB, Price GC, Farrant JK, Subramaniam D, Adeagbo-Sheikh J, Austen BM. Statins inhibit the dimerization of beta-secretase via both isoprenoid- and cholesterol-mediated mechanisms. Biochem J. 2006;399:205–14.CrossRefPubMedPubMedCentral
16.
Onyango IG, Tuttle JB, Bennett Jr JP. Altered intracellular signaling and reduced viability of Alzheimer's disease neuronal cybrids is reproduced by beta-amyloid peptide acting through receptor for advanced glycation end products (RAGE). Mol Cell Neurosci. 2005;29:333–43.CrossRefPubMed
17.
Onyango IG, Bennett Jr JP, Tuttle JB. Endogenous oxidative stress in sporadic Alzheimer's disease neuronal cybrids reduces viability by increasing apoptosis through pro-death signaling pathways and is mimicked by oxidant exposure of control cybrids. Neurobiol Dis. 2005;19:312–22.CrossRefPubMed
18.
Urbich C, Dernbach E, Zeiher AM, Dimmeler S. Double-edged role of statins in angiogenesis signaling. Circ Res. 2002;90:737–44.CrossRefPubMed
19.
Johnson-Anuna LN, Eckert GP, Franke C, Igbavboa U, Muller WE, Wood WG. Simvastatin protects neurons from cytotoxicity by up-regulating Bcl-2 mRNA and protein. J Neurochem. 2007;101:77–86.CrossRefPubMed
20.
Bate C, Williams A. Squalestatin protects neurons and reduces the activation of cytoplasmic phospholipase A2 by Abeta(1–42). Neuropharmacology. 2007;53:222–31.CrossRefPubMed
21.
Bellosta S, Via D, Canavesi M, Pfister P, Fumagalli R, Paoletti R, et al. HMG-CoA reductase inhibitors reduce MMP-9 secretion by macrophages. Arterioscler Thromb Vasc Biol. 1998;18:1671–8.CrossRefPubMed
22.
Frears ER, Stephens DJ, Walters CE, Davies H, Austen BM. The role of cholesterol in the biosynthesis of beta-amyloid. Neuroreport. 1999;10:1699–705.CrossRefPubMed
23.
Wilson SH, Herrmann J, Lerman LO, Holmes Jr DR, Napoli C, Ritman EL, et al. Simvastatin preserves the structure of coronary adventitial vasa vasorum in experimental hypercholesterolemia independent of lipid lowering. Circulation. 2002;105:415–8.CrossRefPubMed
24.
Simons M, Schwarzler F, Lutjohann D, von Bergmann K, Beyreuther K, Dichgans J, et al. Treatment with simvastatin in normocholesterolemic patients with Alzheimer's disease: A 26-week randomized, placebo-controlled, double-blind trial. Ann Neurol. 2002;52:346–50.CrossRefPubMed
25.
Sjogren M, Gustafsson K, Syversen S, Olsson A, Edman A, Davidsson P, et al. Treatment with simvastatin in patients with Alzheimer's disease lowers both alpha- and beta-cleaved amyloid precursor protein. Dement Geriatr Cogn Disord. 2003;16:25–30.CrossRefPubMed
26.
Friedhoff LT, Cullen EI, Geoghagen NS, Buxbaum JD. Treatment with controlled-release lovastatin decreases serum concentrations of human beta-amyloid (A beta) peptide. Int J Neuropsychopharmacol. 2001;4:127–30.CrossRefPubMed
27.
Zhu X, Smith MA, Perry G, Aliev G. Mitochondrial failures in Alzheimer's disease. Am J Alzheimers Dis Other Demen. 2004;19:345–52.CrossRefPubMed
28.
Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci U S A. 1998;95:11715–20.CrossRefPubMedPubMedCentral
29.
30.
Parsons RB, Farrant JK, Price GC, Subramaniam D, Austen BM. Regulation of the lipidation of beta-secretase by statins. Biochem Soc Trans. 2007;35:577–82.CrossRefPubMed
31.
Tamagno E, Bardini P, Obbili A, Vitali A, Borghi R, Zaccheo D, et al. Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiol Dis. 2002;10:279–88.CrossRefPubMed
32.
Kao SC, Krichevsky AM, Kosik KS, Tsai LH. BACE1 suppression by RNA interference in primary cortical neurons. J Biol Chem. 2004;279:1942–9.CrossRefPubMed
Metadata
Title
Dose-specific effect of simvastatin on hypoxia-induced HIF-1α and BACE expression in Alzheimer’s disease cybrid cells
Authors
Jin-Heon Jeong
Kyu Sun Yum
Jun Young Chang
Manho Kim
Jin-young Ahn
SangYun Kim
Paul A Lapchak
Moon-Ku Han
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Neurology / Issue 1/2015
Electronic ISSN: 1471-2377
DOI
https://doi.org/10.1186/s12883-015-0390-5

Other articles of this Issue 1/2015

BMC Neurology 1/2015 Go to the issue

Study protocol

Assessment of immune functions and MRI disease activity in relapsing-remitting multiple sclerosis patients switching from natalizumab to fingolimod (ToFingo-Successor)

Research article

A novel homozygous MPV17 mutation in two families with axonal sensorimotor polyneuropathy

Case report

When battery exhaustion lets the lame walk: a case report on the importance of long-term stimulator monitoring in deep brain stimulation

Case report

Comprehensive diagnostics in a case of hereditary diffuse leukodystrophy with spheroids

Erratum

Erratum to: Olfactory dysfunction in chronic stroke patients

Research article

Factors for short-term outcomes in patients with a minor stroke: results from China National Stroke Registry