Regulation of β amyloid protein level in the brain

Abstract

Abstract: β amyloid protein (Aβ) including Aβ₄₀ and Aβ₄₂ are the important bioactive substances in vivo.Their toxic and beneficial attributes in the body depend on its concentration.The brain Aβ level is maintained by two balances under the physiological condition.The first balance is the generation involved in β-secretase and γ-secretase and the degradation involved in neprilysin (NEP) and insulin-degrading enzyme (IDE) of Aβ.The second one is the balance between the receptor for advanced end glycation products (RAGE)-mediated influx and low-density lipoprotein receptor related protein 1 (LRP1)-mediated eff lux of Aβ across the blood-brain barrier (BBB).Breakdowning any one of the two balances would result in the aggregation and precipitation of Aβ in the brain, which is a crucial event in the pathogenesis of Alzheimer's disease (AD).This paper reviews the regulation of brain Aβ level under the physiological condition and the reducing strategies on the level of brain Aβ under the pathological condition for developing new drugs in the treatment of AD.

Key words: β secretase, γsecretase, neprilysin, insulin-degrading enzyme, receptor for advanced end glycation products (RAGE), low-density lipoprotein receptor related protein 1 (LRP1)

CLC Number:

R338

WANG Ying-yu, WU Jing, HONG Hao, JI Hui, WU Yu-lin. Regulation of β amyloid protein level in the brain[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2009, 14(6): 711-714.

References

[1] Pearson HA, Peers C.Physiological roles for amyloid βpeptides[J].J Physiol, 2006, 575(Pt 1):5-10.
[2] Blennow K, de LeonMJ, Zetterberg H.Alzheimer's disease[J].Lancet, 368(9533):387-403.
[3] Glenner GG, Wong CW.Alzheimer's disease:initial report of the purification and characterization of a novel cerebrovascular amyloid protein[J].Biochem Biophys Res Commun, 1984, 120(3):885-890.
[4] Wong CW, Quaranta V, Glenner GG.Neuritic plaques and cerebrovascular amyloid in Alzheimer disease are antigenically related[J].Proc Natl Acad Sci USA, 1985, 82(24):8729-8732.
[5] Kamenetz F, Tomita T, Hsieh H, et al.APP processing and synaptic function[J].Neuron, 2003, 37(6):925-937.
[6] Plant LD, Webster NJ, Boyle JP, et al.Amyloid beta peptide as a physiological modulator of neuronal'A'-type K⁺ current[J].Neurobiol Aging, 2006, 27(11):1673-1683.
[7] Plant LD, Boyle JP, Smith IF, et al.The production of amyloid beta peptide is a critical requirement for the viability of central neurons[J].J Neurosci, 2003, 23(13): 5531-5535.
[8] Dawson GR, Seabrook GR, Zheng H, et al.Age-related cognitive deficits, impaired long-term potentiation and reduction in synaptic marker density in mice lacking the beta-amyloid precursor protein[J].Neuroscience, 1999, 90(1):1-13.
[9] von Koch CS, Zheng H, Chen H, et al.Generation of APLP2 KO mice and early postnatal lethality in APLP2 APP double KO mice[J].Neurobiol Aging, 1997, 18 (6):661-669.
[10] Luo Y, Bolon B, Kahn S, et al.Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal phenotype and abolished beta-amyloid generation[J].Nat Neurosci, 2001, 4(3):231-132.
[11] Varghese J, James PB, Michael JB, et al.Human β-secretase (BACE) and BACE inhibitors [J].J Med Chem, 2003, 46(22):4625-4630.
[12] Turner AJ, Fisk L, Nalivaeva NN.Targeting amyloid-degrading enzymes as therapeutic strategies in neurodegeneration[J].Ann N Y Acad Sci, 2004, 1035:1-20.
[13] Selkoe DJ, Schenk D.Alzheimer's disease:molecular understanding predicts amyloid-based therapeutics[J]. Annu Rev Pharmacol Toxicol, 2003, 43:545-584.
[14] Shibata M, Yamada S, Kumar SR, et al.Clearance of Alzhermer's amyloid-β₁-40 peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier[J].J Clin Invest, 2000, 106(12):1489-1499.
[15] Deane R, Du Yan S, Submamaryan RK, et al.RAGE mediates amyloid-β peptide transport across the bloodbrain barrier and accumulation in brain[J].Nature Med, 2003, 9(7):907-913.
[16] Deane R, Wu Z, Zlokovic BV.RAGE (Yin) versus LRP (Yang) balance regulates Alzheimer's amyloid β-peptide clearance through transport across the blood-brain barrier [J].Stroke, 2004, 35(11 Suppl 1):2628-2631.
[17] Ghosh AK, Gemma S, Tang J.beta-Secretase as a therapeutic target for Alzheimer's disease[J].Neurotherapeutics, 2008, 5(3):399-408.
[18] Olson RE, Albright CF.Recent progress in the medicinal chemistry of gamma-secretase inhibitors [J].Curr Top Med Chem, 2008, 8(1):17-33.
[19] Cuello AC, Bell KFS.Strategies to diminish the Aβ load in Alzheimer's disease[J].Curr Med Chem-Central Nervous System Agents, 2005, 5(1):15-28.
[20] Jiang Q, Lee CY, Mandrekar S, et al.ApoE promotes the proteolytic degradation of Abeta[J].Neuron, 2008, 58 (5):681-693.
[21] Arvanitakis Z, Grodstein F, Bienias JL, et al.Relation of NSAIDs to incident AD, change in cognitive function, and AD pathology[J].Neurology, 2008, 70 (23):2219-2225.
[22] Jiang Q, Heneka M, Landreth GE.The role of peroxisome proliferator-activated receptor-gamma (PPARgamma) in Alzheimer's disease:therapeutic implications[J].CNS Drugs, 2008, 22(1):1-14.
[23] Shumaker SA, Legault C, Kuller L, et al.Women's Health Initiative Memory Study.Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women:Women's Health Initiative Memory Study[J].JAMA, 2004, 291 (24):2947-2958.
[24] Ni Y, Zhao X, Bao G, et al.Activation of beta 2-adrenergic receptor stimulates gamma-secretase activity and accelerates amyloid plaque formation[J].Nat Med, 2006, 12(12):1390-1396.
[25] Hoshino T, Nakay a T, Homan T, et al.Involvement of prostaglandin E2 in production of amy loid-beta peptides both in vitro and in vivo[J].J Biol Chem, 2007, 282 (45):32676-32688.
[26] He P, Zhong Z, Lindholm K, et al.Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer's mice[J].J Cell Biol, 2007, 178(5):829-841.