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01-07-2005 | Research Article

Statin treatment and a disease-specific pattern of β-amyloid peptides in Alzheimer’s disease

Authors: Kina Höglund, Steinar Syversen, Piotr Lewczuk, Anders Wallin, Jens Wiltfang, Kaj Blennow

Published in: Experimental Brain Research | Issue 2/2005

Abstract

According to the amyloid cascade hypothesis, sporadic Alzheimer’s disease (AD) is caused by the production and aggregation of β-amyloid (Aβ), and the production of Aβ has recently been linked to the metabolism of cholesterol. We have previously published clinical studies where the effect of statin treatment on Aβ production has been investigated. No effect on Aβ was found, which is in disagreement with cell and animal studies. In the present study we investigated the effect of statin treatment on a disease-specific pattern consisting of a C-terminally-truncated quintet of Aβ peptides. Nineteen patients with AD were treated with simvastatin for 12 months and the quintet of Aβ peptides were analysed in cerebrospinal fluid before and after treatment. Also included was a group of 15 untreated patients with AD. We found that the Aβ peptide pattern at baseline was in agreement with earlier findings; however, we did not find any change in the Aβ peptide pattern after statin treatment. We suggest that clinical studies with extended treatment periods are performed where higher dosages of statins are used. We also believe that the pleiotropic effects of statins should be investigated further in order to elucidate the connection between Alzheimer’s disease and statin treatment.

Andreasen N, Blennow K (2002) Beta-amyloid (Abeta) protein in cerebrospinal fluid as a biomarker for Alzheimer’s disease. Peptides 23:1205–1214CrossRefPubMed

Andreasen N, Hesse C, Davidsson P, Minthon L, Wallin A, Winblad B, Vanderstichele H, Vanmechelen E, Blennow K (1999) Cerebrospinal fluid beta-amyloid(1–42) in Alzheimer disease: differences between early- and late-onset Alzheimer disease and stability during the course of disease. Arch Neurol 56:673–680CrossRefPubMed

Björkhem I, Lütjohann D, Diczfalusy U, Stahle L, Ahlborg G, Wahren J (1998) Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation. J Lipid Res 39:1594–1600PubMed

Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley KA, Gerhart M, Davis R, Fitzner JN, Johnson RS, Paxton RJ, March CJ, Cerretti DP (1997) A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 385:729–733CrossRefPubMed

Blennow K, Hampel H (2003) CSF markers for incipient Alzheimer’s disease. Lancet Neurol 2:605–613CrossRefPubMed

Blennow K, Ricksten A, Prince JA, Brookes AJ, Emahazion T, Wasslavik C, Bogdanovic N, Andreasen N, Batsman S, Marcusson J, Nagga K, Wallin A, Regland B, Olofsson H, Hesse C, Davidsson P, Minthon L, Jansson A, Palmqvist L, Rymo L (2000) No association between the alpha2-macroglobulin (A2M) deletion and Alzheimer’s disease, and no change in A2M mRNA, protein, or protein expression. J Neural Transm 107:1065–1079CrossRefPubMed

Bodovitz S, Klein WL (1996) Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein. J Biol Chem 271:4436–4440CrossRefPubMed

Bunce D, Fratiglioni L, Small BJ, Winblad B, Backman L (2004) APOE and cognitive decline in preclinical Alzheimer disease and non-demented aging. Neurology 63:816–821PubMed

Buxbaum JD, Liu KN, Luo Y, Slack JL, Stocking KL, Peschon JJ, Johnson RS, Castner BJ, Cerretti DP, Black RA (1998) Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J Biol Chem 273:27765–27767CrossRefPubMed

Checler F (1995) Processing of the beta-amyloid precursor protein and its regulation in Alzheimer’s disease. J Neurochem 65:1431–1444PubMed

Chochina SV, Avdulov NA, Igbavboa U, Cleary JP, O’Hare EO, Wood WG (2001) Amyloid beta-peptide(1–40) increases neuronal membrane fluidity. Role of cholesterol and brain region. J Lipid Res 42:1292–1297PubMed

De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F (1998) Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391:387–390CrossRefPubMed

Farzan M, Schnitzler CE, Vasilieva N, Leung D, Choe H (2000) BACE2, a beta-secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein. Proc Natl Acad Sci USA 97:9712–9717CrossRefPubMed

Fassbender K, Simons M, Bergmann C, Stroick M, Lütjohann D, Keller P, Runz H, Kühl S, Bertsch T, von Bergmann K, Hennerici M, Beyreuther K, Hartmann T (2001) Simvastatin strongly reduces levels of Alzheimer’s disease beta-amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci USA 98:5856–5861CrossRefPubMed

Fassbender K, Stroick M, Bertsch T, Ragoschke A, Kuehl S, Walter S, Walter J, Brechtel K, Muehlhauser F, Von Bergmann K, Lütjohann D (2002) Effects of statins on human cerebral cholesterol metabolism and secretion of Alzheimer amyloid peptide. Neurology 59:1257–1258PubMed

Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198CrossRefPubMed

Frears ER, Stephens DJ, Walters CE, Davies H, Austen BM (1999) The role of cholesterol in the biosynthesis of beta-amyloid. Neuroreport 10:1699–1705PubMed

Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499–502PubMed

Friedhoff LT, Cullen EI, Geoghagen NS, Buxbaum JD (2001) Treatment with controlled-release lovastatin decreases serum concentrations of human beta-amyloid (A beta) peptide. Int J Neuropsychopharmacol 4:127–130CrossRefPubMed

Hartmann T, Bieger SC, Bruhl B, Tienari PJ, Ida N, Allsop D, Roberts GW, Masters CL, Dotti CG, Unsicker K, Beyreuther K (1997) Distinct sites of intracellular production for Alzheimer’s disease A beta40/42 amyloid peptides. Nat Med 3:1016–1020CrossRefPubMed

Höglund K, Wiklund O, Vanderstichele H, Eikenberg O, Vanmechelen E, Blennow K (2004) Plasma levels of beta-amyloid(1–40), beta-amyloid(1–42), and total beta-amyloid remain unaffected in adult patients with hypercholesterolemia after treatment with statins. Arch Neurol 61:333–337CrossRefPubMed

Höglund K, Thelen K, Syversen S et al (2005) The effect of simvastatin treatment on the amyloid precursor protein in patients with Alzheimer’s disease. Dement Geriatr Cogn Disord 19:256–265CrossRefPubMed

Ida N, Hartmann T, Pantel J, Schroder J, Zerfass R, Forstl H, Sandbrink R, Masters CL, Beyreuther K (1996) Analysis of heterogeneous A4 peptides in human cerebrospinal fluid and blood by a newly developed sensitive western blot assay. J Biol Chem 271:22908–22914CrossRefPubMed

Ishii K, Tokuda T, Matsushima T, Miya F, Shoji S, Ikeda S, Tamaoka A (2003) Pravastatin at 10 mg/day does not decrease plasma levels of either amyloid-beta (Abeta) 40 or Abeta 42 in humans. Neurosci Lett 350:161–164CrossRefPubMed

Iwatsubo T, Mann DM, Odaka A, Suzuki N, Ihara Y (1995) Amyloid beta protein (A beta) deposition: A beta 42(43) precedes A beta 40 in Down syndrome. Ann Neurol 37:294–299CrossRefPubMed

Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA (2000) Statins and the risk of dementia. Lancet 356:1627–1631CrossRefPubMed

Kirsch C, Eckert GP, Mueller WE (2003) Statin effects on cholesterol micro-domains in brain plasma membranes. Biochem Pharmacol 65:843–856CrossRefPubMed

Koike H, Tomioka S, Sorimachi H, Saido TC, Maruyama K, Okuyama A, Fujisawa-Sehara A, Ohno S, Suzuki K, Ishiura S (1999) Membrane-anchored metalloprotease MDC9 has an alpha-secretase activity responsible for processing the amyloid precursor protein. Biochem J 343(Pt 2):371–375CrossRefPubMed

Kojro E, Gimpl G, Lammich S, Marz W, Fahrenholz F (2001) Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha-secretase ADAM 10. Proc Natl Acad Sci USA 98:5815–5820CrossRefPubMed

Lammich S, Kojro E, Postina R, Gilbert S, Pfeiffer R, Jasionowski M, Haass C, Fahrenholz F (1999) Constitutive and regulated alpha-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease. Proc Natl Acad Sci USA 96:3922–3927CrossRefPubMed

Lewczuk P, Esselmann H, Meyer M, Wollscheid V, Neumann M, Otto M, Maler JM, Ruther E, Kornhuber J, Wiltfang J (2003) The amyloid-beta (Abeta) peptide pattern in cerebrospinal fluid in Alzheimer’s disease: evidence of a novel carboxyterminally elongated Abeta peptide. Rapid Commun Mass Spectrom 17:1291–1296CrossRefPubMed

Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, Beach T, Kurth JH, Rydel RE, Rogers J (1999) Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. Am J Pathol 155:853–862PubMed

Mason RP, Jacob RF, Walter MF, Mason PE, Avdulov NA, Chochina SV, Igbavboa U, Wood WG (1999) Distribution and fluidizing action of soluble and aggregated amyloid beta-peptide in rat synaptic plasma membranes. J Biol Chem 274:18801–18807CrossRefPubMed

McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944PubMed

McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, Bush AI, Masters CL (1999) Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann Neurol 46:860–866CrossRefPubMed

Michikawa M, Gong JS, Fan QW, Sawamura N, Yanagisawa K (2001) A novel action of Alzheimer’s amyloid beta-protein (Abeta): oligomeric Abeta promotes lipid release. J Neurosci 21:7226–7235PubMed

Mills J, Reiner PB (1999) Regulation of amyloid precursor protein cleavage. J Neurochem 72:443–460CrossRefPubMed

Mohs RC, Cohen L (1988) Alzheimer’s Disease Assessment Scale (ADAS). Psychopharmacol Bull 24:627–628PubMed

Moss ML, Jin SL, Milla ME, Bickett DM, Burkhart W, Carter HL, Chen WJ, Clay WC, Didsbury JR, Hassler D, Hoffman CR, Kost TA, Lambert MH, Leesnitzer MA, McCauley P, McGeehan G, Mitchell J, Moyer M, Pahel G, Rocque W, Overton LK, Schoenen F, Seaton T, Su JL, Becherer JD et al (1997) Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature 385:733–736CrossRefPubMed

Ohlsson A, Vanderstichele H, Andreasen N, Demeyer G, Holmberg G, Rosengren L, Vanmechelen E, Blennow K (2005) Simultaneous measurement of beta-amyloid(1–42), total tau and phosphorylated tau (Thr181) in cerebrospinal fluid using the xMAP technology. Clin Chem 51(2):336–345CrossRefPubMed

Park IH, Hwang EM, Hong HS, Boo JH, Oh SS, Lee J, Jung MW, Bang OY, Kim SU, Mook-Jung I (2003) Lovastatin enhances Abeta production and senile plaque deposition in female Tg2576 mice. Neurobiol Aging 24:637–643CrossRefPubMed

Rockwood K, Kirkland S, Hogan DB, MacKnight C, Merry H, Verreault R, Wolfson C, McDowell I (2002) Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch Neurol 59:223–227CrossRefPubMed

Runz H, Rietdorf J, Tomic I, de Bernard M, Beyreuther K, Pepperkok R, Hartmann T (2002) Inhibition of intracellular cholesterol transport alters presenilin localization and amyloid precursor protein processing in neuronal cells. J Neurosci 22:1679–1689PubMed

Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S (1996) Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med 2:864–870CrossRefPubMed

Shi XP, Tugusheva K, Bruce JE, Lucka A, Wu GX, Chen-Dodson E, Price E, Li Y, Xu M, Huang Q, Sardana MK, Hazuda DJ (2003) Beta-secretase cleavage at amino acid residue 34 in the amyloid beta peptide is dependent upon gamma-secretase activity. J Biol Chem 278:21286–21294CrossRefPubMed

Simons M, Keller P, De Strooper B, Beyreuther K, Dotti CG, Simons K (1998) Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci USA 95:6460–6464PubMed

Simons M, Schwarzler F, Lütjohann D, von Bergmann K, Beyreuther K, Dichgans J, Wormstall H, Hartmann T, Schulz JB (2002) Treatment with simvastatin in normocholesterolemic patients with Alzheimer’s disease: a 26-week randomized, placebo-controlled, double-blind trial. Ann Neurol 52:346–350CrossRefPubMed

Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, Frigon N, Hong J, Jacobson-Croak K, Jewett N, Keim P, Knops J, Lieberburg I, Power M, Tan H, Tatsuno G, Tung J, Schenk D, Seubert P, Suomensaari SM, Wang S, Walker D, John V et al (1999) Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 402:537–540CrossRefPubMed

Sjögren M, Gustafsson K, Syversen S, Olsson A, Edman A, Davidsson P, Wallin A, Blennow K (2003) Treatment with Simvastatin in patients with Alzheimer’s disease lowers both alpha- and beta-cleaved amyloid precursor protein. Dement Geriatr Cogn Disord 16:25–30PubMed

Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (1993a) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 90:1977–1981

Strittmatter WJ, Weisgraber KH, Huang DY, Dong LM, Salvesen GS, Pericak-Vance M, Schmechel D, Saunders AM, Goldgaber D, Roses AD (1993b) Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci USA 90:8098–8102

Tokuda T, Tamaoka A, Matsuno S, Sakurai S, Shimada H, Morita H, Ikeda S (2001) Plasma levels of amyloid beta proteins did not differ between subjects taking statins and those not taking statins. Ann Neurol 49:546–547CrossRefPubMed

Tomita S, Kirino Y, Suzuki T (1998) A basic amino acid in the cytoplasmic domain of Alzheimer’s beta-amyloid precursor protein (APP) is essential for cleavage of APP at the alpha-site. J Biol Chem 273:19304–19310CrossRefPubMed

Urmoneit B, Turner J, Dyrks T (1998) Cationic lipids (lipofectamine) and disturbance of cellular cholesterol and sphingomyelin distribution modulates gamma-secretase activity within amyloid precursor protein in vitro. Prostaglandins Other Lipid Mediat 55:331–343PubMed

Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735–741CrossRefPubMed

Wahrle S, Das P, Nyborg AC, McLendon C, Shoji M, Kawarabayashi T, Younkin LH, Younkin SG, Golde TE (2002) Cholesterol-dependent gamma-secretase activity in buoyant cholesterol-rich membrane microdomains. Neurobiol Dis 9:11–23CrossRefPubMed

Weidemann A, Eggert S, Reinhard FB, Vogel M, Paliga K, Baier G, Masters CL, Beyreuther K, Evin G (2002) A novel epsilon-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with Notch processing. Biochemistry 41:2825–2835CrossRefPubMed

Wiltfang J, Arold N, Neuhoff V (1991) A new multiphasic buffer system for sodium dodecyl sulfate-polyacrylamide gel electrophoresis of proteins and peptides with molecular masses 100,000–1,000, and their detection with picomolar sensitivity. Electrophoresis 12:352–366CrossRefPubMed

Wiltfang J, Smirnov A, Schnierstein B, Kelemen G, Matthies U, Klafki HW, Staufenbiel M, Huther G, Ruther E, Kornhuber J (1997) Improved electrophoretic separation and immunoblotting of beta-amyloid (A beta) peptides 1–40, 1–42, and 1–43. Electrophoresis 18:527–532CrossRefPubMed

Wiltfang J, Esselmann H, Cupers P, Neumann M, Kretzschmar H, Beyermann M, Schleuder D, Jahn H, Ruther E, Kornhuber J, Annaert W, De Strooper B, Saftig P (2001) Elevation of beta-amyloid peptide 2–42 in sporadic and familial Alzheimer’s disease and its generation in PS1 knockout cells. J Biol Chem 276:42645–42657CrossRefPubMed

Wiltfang J, Esselmann H, Bibl M, Smirnov A, Otto M, Paul S, Schmidt B, Klafki HW, Maler M, Dyrks T, Bienert M, Beyermann M, Ruther E, Kornhuber J (2002) Highly conserved and disease-specific patterns of carboxyterminally truncated Abeta peptides 1–37/38/39 in addition to 1–40/42 in Alzheimer’s disease and in patients with chronic neuroinflammation. J Neurochem 81:481–496CrossRefPubMed

Wisniewski KE, Dalton AJ, McLachlan C, Wen GY, Wisniewski HM (1985) Alzheimer’s disease in Down’s syndrome: clinicopathologic studies. Neurology 35:957–961PubMed

Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G (2000) Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol 57:1439–1443CrossRefPubMed

Yaffe K, Barrett-Connor E, Lin F, Grady D (2002) Serum lipoprotein levels, statin use, and cognitive function in older women. Arch Neurol 59:378–384CrossRefPubMed

Yamaguchi H, Maat-Schieman ML, van Duinen SG, Prins FA, Neeskens P, Natte R, Roos RA (2000) Amyloid beta protein (Abeta) starts to deposit as plasma membrane-bound form in diffuse plaques of brains from hereditary cerebral hemorrhage with amyloidosis-Dutch type, Alzheimer disease and nondemented aged subjects. J Neuropathol Exp Neurol 59:723–732PubMed

Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, Carter DB, Tomasselli AG, Parodi LA, Heinrikson RL, Gurney ME (1999) Membrane-anchored aspartyl protease with Alzheimer’s disease beta-secretase activity. Nature 402:533–537CrossRefPubMed

Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A, Song YQ, Rogaeva E, Chen F, Kawarai T, Supala A, Levesque L, Yu H, Yang DS, Holmes E, Milman P, Liang Y, Zhang DM, Xu DH, Sato C, Rogaev E, Smith M, Janus C, Zhang Y, Aebersold R, Farrer LS, Sorbi S, Bruni A, Fraser P, St George-Hyslop P (2000) Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature 407:48–54CrossRefPubMed

Title: Statin treatment and a disease-specific pattern of β-amyloid peptides in Alzheimer’s disease
Authors: Kina Höglund
Steinar Syversen
Piotr Lewczuk
Anders Wallin
Jens Wiltfang
Kaj Blennow
Publication date: 01-07-2005
Publisher: Springer-Verlag
Published in: Experimental Brain Research / Issue 2/2005
Print ISSN: 0014-4819
Electronic ISSN: 1432-1106
DOI: https://doi.org/10.1007/s00221-005-2243-8

Keynote webinar | Spotlight on medication adherence

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Statin treatment and a disease-specific pattern of β-amyloid peptides in Alzheimer’s disease

Abstract

Keynote webinar | Spotlight on medication adherence

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Abstract

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