Inhibition of tau hyperphosphorylation and beta amyloid production in rat brain by oral administration of atorvastatin
- Author:
- No author available
- Journal Title:
- CHINESE MEDICAL JOURNAL
- Issue:
- 14
- DOI:
- 10.3760/cma.j.issn.0366-6999.2010.14.007
- Key Word:
- Alzheimer's disease;cholesterol;tau;β-amyloid;atorvastatin
Abstract： Background Alzheimer's disease (AD) is a neurodegenerative disorder and the leading cause of dementia in the elderly. The two hallmark lesions in AD brain are deposition of amyloid plaques and neurofibrillary tangles (NFTs).Hypercholesteremia is one of the risk factors of AD. But its role in the pathogenesis of AD is largely unknown. The aim of this study was to investigate the relationship between hypercholesteremia and tau phosphorylation or β-amyloid (Aβ),and evaluate the effect of atorvastatin on the level of tau phosphorylation and Aβ in the brains of rats fed with high cholesterol diet.Methods Sprague-Dawley (SD) rats were randomly divided into normal diet control group, high cholesterol diet group,and high cholesterol diet plus atorvastatin (Lipitor, 15 mg·kg-1·d-1) treated group. Blood from caudal vein was collected to measure total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL) and high-density lipoprotein (HDL) at the end of the 3th and the 6th months by an enzymatic method. The animals were sacrificed 6 months later and brains were removed. All left brain hemispheres were fixed for immunohistochemistry. Hippocampus and cerebral cortex were separated from right hemispheres and homogenized separately. Tau phosphorylation and Aβ in the brain tissue were determined by Western blotting (using antibodies PHF-1 and Tau-1) and anti-Aβ40/anti-Aβ42, respectively.Results We found that high cholesterol diet led to hypercholesteremia of rats as well as hyperphosphorylation of tau and increased Aβ level in the brains. Treatment of the high cholesterol diet fed rats with atorvastatin prevented the changes of both tau phosphorylation and Aβ level induced by high cholesterol diet.Conclusions Hypercholesteremia could induce tau hyperphosphorylation and Aβ production in rat brain. Atorvastatin could inhibit tau hyperphosphorylation and decrease Aβ generation. It may play a protective role in the patho-process of hypercholesteremia-induced neurodegeneration in the brain.
- [1]D L, Sparks,S W, Scheff,J C, Hunsaker,etc.Induction of Alzheimer-like beta-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol.[J].1994,126(1).
- [2]Mehdi Shishehbor,Marie-Luise Brennan,Ronnier Aviles,etc.Statins Promote Potent Systemic Antioxidant Effects Through Specific Inflammatory Pathways[J].2003,108(4).
- [3]Anstey KJ,Low LF,Lipnicki DM.Cholesterol as a risk factor for dementia and cognitive decline: a systematic review of prospective studies with meta-analysis.[J].2008,16(5).
- [4]Sawsan, Youssef,Olaf, Stüve,Juan C, Patarroyo,etc.The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease.[J].2002,420(6911).
- [5]Landreth G,Cordle A.3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors attenuate beta-amyloid-induced microglial inflammatory responses.[J].2005,25(2).
- [6]Small G. W..Diagnosis and treatment of Alzheimer disease and related disorders. Consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society[J].1997.
- [7]Meske V,Albert F,Harzer K,etc.Cholesterol storage and tau pathology in Niemann-Pick type C disease in the brain.[J].2003,200(1).
- [8]Koudinov AR,Koudinova NV.Cholesterol homeostasis failure as a unifying cause of synaptic degeneration.[J].2005,229/230(0).
- [9]Teresa Proenga,Ana Catarina R.G. Fonseca,Rosa Resende.Neuroprotective Effects of Statins in an In Vitro Model of Alzheimer's Disease[J].2009,17(3).
- [10]Kiener PA ms.com,Rankin BM,Youssef S,etc.Stimulation of inflammatory responses in vitro and in vivo by lipophilic HMG-CoA reductase inhibitors.[J].2001,1(1).
- [11]Love, S.,Bridges, L. R.,Case, C. P..Neurofibrillary tangles in Niemann-Pick disease type C[J].1995,118(1).
- [12]Jenkins EC,Silverman W,Urv TK,etc.Cholesterol level, statin use and Alzheimer's disease in adults with Down syndrome.[J].2007,416(3).
- [13]LaFrancois J,Matsuoka Y,Mercken M,etc.Presenilin redistribution associated with aberrant cholesterol transport enhances beta-amyloid production in vivo.[J].2003,23(13).
- [14]Jesús, Avila,Félix, Hernández.GSK-3 inhibitors for Alzheimer's disease.[J].2007,7(11).
- [15]Lee MS,Tsai LH.Cdk5: One of the links between senile plaques and neurofibrillary tangles?[J].2003,5(2).
- [16]I L, Notkola,R, Sulkava,J, Pekkanen,etc.Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease.[J].1998,17.
- [17]Manjon M,Girones X,Wolozin B,etc.Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology.[J].2003,61(2).
- [18]Sandra Kalmijn,Lenore J. Launer,Alewijn Ott,etc.Dietary fat intake and the risk of incident dementia in the Rotterdam study[J].1997,42(5).
- [19]Lovestone S,Mudher A.Alzheimer's disease-do tauists and baptists finally shake hands?[J].2002,25(1).
- [20]Lloyd D,Furlong S,Zacco A,etc.3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors protect cortical neurons from excitotoxicity.[J].2003,23(35).
- [21]Williams A,Bate C.Squalestatin protects neurons and reduces the activation of cytoplasmic phospholipase A2 by Abeta(1-42).[J].2007,53(2).
- [22]Verdile G,Chan HW,Perry G,etc.Amyloid-beta-induced toxicity of primary neurons is dependent upon differentiation-associated increases in tau and cyclin-dependent kinase 5 expression.[J].2004,88(3).
- [23]Kitazawa M,Oddo S,LaFerla FM,etc.Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease.[J].2003,24(8).
- [24]Alonso- A,Zaidi T,Novak M,etc.Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments.[J].2001,98(12).
- [25]Ye J,Lange Y,Rigney M,etc.Regulation of endoplasmic reticulum cholesterol by plasma membrane cholesterol.[J].1999,40(12).
- [26]Johnson MD,Allen GS,Okediji EJ,etc.Lovastatin is a potent inhibitor of meningioma cell proliferation: evidence for inhibition of a mitogen associated protein kinase.[J].2002,56(2).
- [27]Haass C,Ehehalt R,Thiele C,etc.Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts.[J].2003,160(1).
- [28]Ohm TG,Schonheit B,Zarski R.Spatial and temporal relationships between plaques and tangles in Alzheimer-pathology.[J].2004,25(6).
- [29]Auer, I. A.,Schmidt, M. L.,Lee, V. M.-Y.,etc.Paired helical filament tau (PHFtau) in Niemann-Pick type C disease is similar to PHFtau in Alzheimer's disease[J].1995,90(6).
- [30]Soininen H,Tuomilehto J,Helkala EL,etc.Midlife vascular risk factors and late-life mild cognitive impairment: A population-based study.[J].2001,56(12).
- [31]Venu T, Tadiboyina,Dora M, Liu,Brooke A, Miskie,etc.Treatment of dyslipidemia with lovastatin and ezetimibe in an adolescent with cholesterol ester storage disease.[J].2005,4.
- [32]Rojiani AM,Crawford F,Paris D,etc.Cholesterol accumulates in senile plaques of Alzheimer disease patients and in transgenic APP(SW) mice.[J].2001,60(8).
- [33]Runz H,Stroick M,Keller P,etc.Simvastatin strongly reduces levels of Alzheimer's disease beta -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo.[J].2001,98(10).
- [34]Oddo S,Kayed R,LaFerla FM,etc.Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction.[J].2003,39(3).
- [35]Hommel U,Cottens S,Welzenbach K,etc.Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site.[J].2001,7(6).
- [36]Gellermann GP,Ullrich K,Tannert A,etc.Alzheimer-like plaque formation by human macrophages is reduced by fibrillation inhibitors and lovastatin[J].2006,360(2).
- [37]Lee KY,Rosales JL,Fung T,etc.Elevated neuronal Cdc2-like kinase activity in the Alzheimer disease brain.[J].1999,34(1).
- [38]Tseng HC,Goldman JA,Shih H,etc.Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles.[J].2003,40(3).