The Membrane-Bound Aspartyl Protease BACE1: Molecular and Functional Properties in Alzheimer's Disease and Beyond

Overview

Journal Front Physiol

Date 2012 Feb 25

PMID 22363289

Citations 41

Authors

Bastian Dislich

Stefan F Lichtenthaler

Affiliations

Soon will be listed here.

Abstract

The β-site APP cleaving enzyme 1 (BACE1) is a transmembrane aspartyl protease involved in Alzheimer's disease (AD) pathogenesis and in myelination. BACE1 initiates the generation of the pathogenic amyloid β-peptide, which makes BACE1 a major drug target for AD. BACE1 also cleaves and activates neuregulin 1, thereby contributing to postnatal myelination, in particular in the peripheral nervous system. Additional proteins are also cleaved by BACE1, but less is known about the physiological consequences of their cleavage. Recently, new phenotypes were described in BACE1-deficient mice. Although it remains unclear through which BACE1 substrates they are mediated, the phenotypes suggest a versatile role of this protease for diverse physiological processes. This review summarizes the enzymatic and cellular properties of BACE1 as well as its regulation by lipids, by transcriptional, and by translational mechanisms. The main focus will be on the recent progress in understanding BACE1 function and its implication for potential mechanism-based side effects upon therapeutic inhibition.

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References

Mei L, Xiong W . Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci. 2008; 9(6):437-52. PMC: 2682371. DOI: 10.1038/nrn2392. View

Irizarry M, Locascio J, Hyman B . beta-site APP cleaving enzyme mRNA expression in APP transgenic mice: anatomical overlap with transgene expression and static levels with aging. Am J Pathol. 2001; 158(1):173-7. PMC: 1850271. DOI: 10.1016/s0002-9440(10)63955-7. View

Kawarabayashi T, Shoji M, Younkin L, Wen-Lang L, Dickson D, Murakami T . Dimeric amyloid beta protein rapidly accumulates in lipid rafts followed by apolipoprotein E and phosphorylated tau accumulation in the Tg2576 mouse model of Alzheimer's disease. J Neurosci. 2004; 24(15):3801-9. PMC: 6729359. DOI: 10.1523/JNEUROSCI.5543-03.2004. View

Sankaranarayanan S, Holahan M, Colussi D, Crouthamel M, Devanarayan V, Ellis J . First demonstration of cerebrospinal fluid and plasma A beta lowering with oral administration of a beta-site amyloid precursor protein-cleaving enzyme 1 inhibitor in nonhuman primates. J Pharmacol Exp Ther. 2008; 328(1):131-40. DOI: 10.1124/jpet.108.143628. View

Chang W, Downs D, Huang X, Da H, Fung K, Tang J . Amyloid-beta reduction by memapsin 2 (beta-secretase) immunization. FASEB J. 2007; 21(12):3184-96. DOI: 10.1096/fj.06-7993com. View

Hook V, Kindy M, Hook G . Inhibitors of cathepsin B improve memory and reduce beta-amyloid in transgenic Alzheimer disease mice expressing the wild-type, but not the Swedish mutant, beta-secretase site of the amyloid precursor protein. J Biol Chem. 2008; 283(12):7745-53. DOI: 10.1074/jbc.M708362200. View

Rodal S, Skretting G, Garred O, Vilhardt F, van Deurs B, Sandvig K . Extraction of cholesterol with methyl-beta-cyclodextrin perturbs formation of clathrin-coated endocytic vesicles. Mol Biol Cell. 1999; 10(4):961-74. PMC: 25220. DOI: 10.1091/mbc.10.4.961. View

Mihailovich M, Thermann R, Grohovaz F, Hentze M, Zacchetti D . Complex translational regulation of BACE1 involves upstream AUGs and stimulatory elements within the 5' untranslated region. Nucleic Acids Res. 2007; 35(9):2975-85. PMC: 1888809. DOI: 10.1093/nar/gkm191. View

Heber S, Herms J, Gajic V, Hainfellner J, Aguzzi A, Rulicke T . Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members. J Neurosci. 2000; 20(21):7951-63. PMC: 6772747. View

10.

Hussain I, Powell D, Howlett D, Chapman G, Gilmour L, Murdock P . ASP1 (BACE2) cleaves the amyloid precursor protein at the beta-secretase site. Mol Cell Neurosci. 2000; 16(5):609-19. DOI: 10.1006/mcne.2000.0884. View

11.

Qing H, Zhou W, Christensen M, Sun X, Tong Y, Song W . Degradation of BACE by the ubiquitin-proteasome pathway. FASEB J. 2004; 18(13):1571-3. DOI: 10.1096/fj.04-1994fje. View

12.

Tun H, Marlow L, Pinnix I, Kinsey R, Sambamurti K . Lipid rafts play an important role in A beta biogenesis by regulating the beta-secretase pathway. J Mol Neurosci. 2002; 19(1-2):31-5. DOI: 10.1007/s12031-002-0007-5. View

13.

Catterall W . From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron. 2000; 26(1):13-25. DOI: 10.1016/s0896-6273(00)81133-2. View

14.

Riddell D, Christie G, Hussain I, Dingwall C . Compartmentalization of beta-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts. Curr Biol. 2001; 11(16):1288-93. DOI: 10.1016/s0960-9822(01)00394-3. View

15.

Faghihi M, Modarresi F, Khalil A, Wood D, Sahagan B, Morgan T . Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase. Nat Med. 2008; 14(7):723-30. PMC: 2826895. DOI: 10.1038/nm1784. View

16.

Rogers Jr G, Edelman G, Mauro V . Differential utilization of upstream AUGs in the beta-secretase mRNA suggests that a shunting mechanism regulates translation. Proc Natl Acad Sci U S A. 2004; 101(9):2794-9. PMC: 365699. DOI: 10.1073/pnas.0308576101. View

17.

Sinha S, Anderson J, Barbour R, Basi G, Caccavello R, Davis D . Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature. 1999; 402(6761):537-40. DOI: 10.1038/990114. View

18.

Costantini C, Ko M, Jonas M, Puglielli L . A reversible form of lysine acetylation in the ER and Golgi lumen controls the molecular stabilization of BACE1. Biochem J. 2007; 407(3):383-95. PMC: 2275071. DOI: 10.1042/BJ20070040. View

19.

Yan R, Bienkowski M, Shuck M, Miao H, Tory M, Pauley A . Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature. 1999; 402(6761):533-7. DOI: 10.1038/990107. View

20.

Cordy J, Hussain I, Dingwall C, Hooper N, Turner A . Exclusively targeting beta-secretase to lipid rafts by GPI-anchor addition up-regulates beta-site processing of the amyloid precursor protein. Proc Natl Acad Sci U S A. 2003; 100(20):11735-40. PMC: 208827. DOI: 10.1073/pnas.1635130100. View