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The Role of Amyloid Precursor Protein Processing by BACE1, the β-Secretase, in Alzheimer Disease Pathophysiology

2008; Elsevier BV; Volume: 283; Issue: 44 Linguagem: Inglês

10.1074/jbc.r800015200

ISSN

1083-351X

Autores

Sarah L. Cole, Robert Vassar,

Tópico(s)

Prion Diseases and Protein Misfolding

Resumo

Amyloid plaques, composed of the amyloid β-protein (Aβ), are hallmark neuropathological lesions in Alzheimer disease (AD) brain. Aβ fulfills a central role in AD pathogenesis, and reduction of Aβ levels should prove beneficial for AD treatment. Aβ generation is initiated by proteolysis of amyloid precursor protein (APP) by the β-secretase enzyme BACE1. Bace1 knockout (Bace1–/–) mice have validated BACE1 as the authentic β-secretase in vivo. BACE1 is essential for Aβ generation and represents a suitable drug target for AD therapy, especially because this enzyme is up-regulated in AD. However, although initial data indicated that Bace1–/– mice lack an overt phenotype, the BACE1-mediated processing of APP and other substrates may be important for specific biological processes. In this minireview, topics range from the initial identification of BACE1 to the fundamental knowledge gaps that remain in our understanding of this protease. We address pertinent questions such as putative causes of BACE1 elevation in AD and discuss why, nine years since the identification of BACE1, treatments that address the underlying pathological mechanisms of AD are still lacking. Amyloid plaques, composed of the amyloid β-protein (Aβ), are hallmark neuropathological lesions in Alzheimer disease (AD) brain. Aβ fulfills a central role in AD pathogenesis, and reduction of Aβ levels should prove beneficial for AD treatment. Aβ generation is initiated by proteolysis of amyloid precursor protein (APP) by the β-secretase enzyme BACE1. Bace1 knockout (Bace1–/–) mice have validated BACE1 as the authentic β-secretase in vivo. BACE1 is essential for Aβ generation and represents a suitable drug target for AD therapy, especially because this enzyme is up-regulated in AD. However, although initial data indicated that Bace1–/– mice lack an overt phenotype, the BACE1-mediated processing of APP and other substrates may be important for specific biological processes. In this minireview, topics range from the initial identification of BACE1 to the fundamental knowledge gaps that remain in our understanding of this protease. We address pertinent questions such as putative causes of BACE1 elevation in AD and discuss why, nine years since the identification of BACE1, treatments that address the underlying pathological mechanisms of AD are still lacking. AD 2The abbreviations used are: AD, Alzheimer disease; FAD, familial AD; APP, amyloid precursor protein; PS, presenilin; TBI, traumatic brain injury; Aβ, amyloid β-protein; APPs, secreted APP; AICD, APP intracellular domain; Tg, transgenic. is the most common form of dementia, afflicting over 29 million people worldwide, a figure anticipated to rise exponentially within decades. Although the etiology remains enigmatic, AD appears to be brought about by both genetic and non-genetic factors. ∼5% of AD cases are familial (FAD), caused by autosomal dominant mutations in either APP or the PS genes. The underlying cause(s) remain elusive for the majority of sporadic AD cases, although specific risk factors have been identified and include aging, the apolipoprotein E4 allele, certain vascular diseases, and TBI (1Cole S.L. Vassar R. Mol. Neurodegener. 2007; 2: 22Crossref PubMed Scopus (365) Google Scholar). Several major pathologies are observed in AD, and the amyloid hypothesis states that Aβ plays a critical early role, triggering a complex pathological cascade that leads to neurodegeneration (2Golde T.E. Dickson D. Hutton M. Curr. Alzheimer Res. 2006; 3: 421-430Crossref PubMed Scopus (124) Google Scholar). A strong genetic correlation exists between FAD and a neurotoxic form of fibrillogenic Aβ, Aβ42 (3Glabe C.G. J. Biol. Chem. 2008; 283: 29639-29643Abstract Full Text Full Text PDF PubMed Scopus (653) Google Scholar). Pre-symptomatic FAD patients exhibit Aβ42 elevations or elevations in Aβ42 levels relative to levels of the less fibrillogenic peptide, Aβ40, indicating that Aβ42 may initiate pathophysiology. Patients with additional copies of the APP gene exhibit total Aβ overproduction and develop early-onset AD (1Cole S.L. Vassar R. Mol. Neurodegener. 2007; 2: 22Crossref PubMed Scopus (365) Google Scholar, 4Rovelet-Lecrux A. Hannequin D. Raux G. Le Meur N. Laquerriere A. Vital A. Dumanchin C. Feuillette S. Brice A. Vercelletto M. Dubas F. Frebourg T. Campion D. Nat. Genet. 2006; 38: 24-26Crossref PubMed Scopus (973) Google Scholar). Data point toward a critical role for Aβ42 in AD etiology, and strategies to lower brain Aβ42 levels should be therapeutically beneficial in AD. Aβ is formed from endoproteolysis of APP, a type 1 membrane protein (Fig. 1) (5Vassar R. J. Mol. Neurosci. 2004; 23: 105-114Crossref PubMed Scopus (303) Google Scholar). BACE1 (β-site APP-cleaving enzyme 1) is essential for initiating Aβ generation and cleaves the APP Asp+1 residue to form the Aβ N terminus, APPsβ, and a C-terminal fragment, C99. BACE1 cleavage of APP is a prerequisite for γ-secretase-mediated cleavage, and C99 is proteolyzed by γ-secretase (a protein complex containing PS), which generates an AICD and Aβ. This imprecise cleavage produces Aβ variants, including those ending at residues 40 (Aβ40) and 42 (Aβ42). Aβ formation is precluded by α-secretase cleavage of APP, within the Aβ domain, which liberates APPsα and the C-terminal fragment C83. γ-Secretase then cleaves C83, forming p3 and an AICD. The α- and β-secretase moieties can compete for APP substrate (6Vassar R. Bennett B.D. Babu-Khan S. Kahn S. Mendiaz E.A. Denis P. Teplow D.B. Ross S. Amarante P. Loeloff R. Luo Y. Fisher S. Fuller J. Edenson S. Lile J. Jarosinski M.A. Biere A.L. Curran E. Burgess T. 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A. 2000; 97: 1456-1460Crossref PubMed Scopus (740) Google Scholar). Neural tissue exhibits maximal β-secretase activity, and astrocytes exhibit less activity than neurons (12Zhao J. Paganini L. Mucke L. Gordon M. Refolo L. Carman M. Sinha S. Oltersdorf T. Lieberburg I. McConlogue L. J. Biol. Chem. 1996; 271: 31407-31411Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). Accordingly, BACE1 mRNA levels are highest in brain, being enriched in neurons but found at low levels in resting glia. The BACE1 protein is abundant in human brain (6Vassar R. Bennett B.D. Babu-Khan S. Kahn S. Mendiaz E.A. Denis P. Teplow D.B. Ross S. Amarante P. Loeloff R. Luo Y. Fisher S. Fuller J. Edenson S. Lile J. Jarosinski M.A. Biere A.L. Curran E. Burgess T. Louis J.-C. Collins F. Treanor J. Rogers G. Citron M. Science. 1999; 286: 735-741Crossref PubMed Scopus (3308) Google Scholar). Like other pepsin family members, BACE1 has two active site motifs, and mutation of either causes inactivity (8Hussain I. Powell D. Howlett D.R. Tew D.G. Meek T.D. Chapman C. Gloger I.S. Murphy K.E. Southan C.D. Ryan D.M. Smith T.S. Simmons D.L. Walsh F.S. Dingwall C. Christie G. Mol. Cell. Neurosci. 1999; 14: 419-427Crossref PubMed Scopus (1001) Google Scholar, 13Bennett B.D. Denis P. Haniu M. Teplow D.B. Kahn S. Louis J.-C. Citron M. Vassar R. J. Biol. Chem. 2000; 275: 37712-37717Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar). BACE1 is a type 1 membrane protease with a single transmembrane domain near its C terminus and a luminal active site that provides the correct topological orientation for APP cleavage at the β-secretase site. As predicted, BACE1 has optimal activity at pH 4.5, being localized within acidic compartments of the secretory pathway (6Vassar R. Bennett B.D. Babu-Khan S. Kahn S. Mendiaz E.A. Denis P. Teplow D.B. Ross S. Amarante P. Loeloff R. Luo Y. Fisher S. Fuller J. Edenson S. Lile J. Jarosinski M.A. Biere A.L. Curran E. Burgess T. Louis J.-C. Collins F. Treanor J. Rogers G. Citron M. Science. 1999; 286: 735-741Crossref PubMed Scopus (3308) Google Scholar). β-Secretase efficiently cleaves only membrane-bound substrates, although this protease can tolerate changes in the distance of the cleaved peptide bond from the membrane (1Cole S.L. Vassar R. Mol. Neurodegener. 2007; 2: 22Crossref PubMed Scopus (365) Google Scholar, 14Citron M. Teplow D.B. Selkoe D.J. Neuron. 1995; 14: 661-670Abstract Full Text PDF PubMed Scopus (233) Google Scholar). BACE1 transfection of APP-overexpressing cells elevates APPsβ, C99, and Aβ levels and reduces APPsα levels. Conversely, BACE1 antisense oligonucleotide treatment inhibits APPsβ, C99, and Aβ production and elevates APPsα and C83 levels (1Cole S.L. Vassar R. Mol. Neurodegener. 2007; 2: 22Crossref PubMed Scopus (365) Google Scholar, 6Vassar R. Bennett B.D. Babu-Khan S. Kahn S. Mendiaz E.A. Denis P. Teplow D.B. Ross S. Amarante P. Loeloff R. Luo Y. Fisher S. Fuller J. Edenson S. Lile J. Jarosinski M.A. Biere A.L. Curran E. Burgess T. Louis J.-C. Collins F. Treanor J. Rogers G. Citron M. Science. 1999; 286: 735-741Crossref PubMed Scopus (3308) Google Scholar). Several Aβ species with different N-terminal residues exist. Aβ isolated from plaques predominantly begins at Asp+1 of Aβ, although minor species begin at Val–3, Ile–6, and Glu+11. Although the Val–3 and Ile–6 species are not generated by β-secretase, BACE1 is responsible for cleaving at both Asp+1 and Glu+11 (1Cole S.L. Vassar R. Mol. Neurodegener. 2007; 2: 22Crossref PubMed Scopus (365) Google Scholar, 15Haass C. Schlossmacher M.G. Hung A.Y. Vigo-Pelfrey C. Mellon A. Ostaszewski B.L. Lieberburg I. Koo E.H. Schenk D. Teplow D.B. Selkoe D.J. Nature. 1992; 359: 322-325Crossref PubMed Scopus (1763) Google Scholar, 16Citron M. Diehl T.S. Capell A. Haass C. Teplow D.B. Selkoe D.J. Neuron. 1996; 17: 171-179Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 17Gouras G.K. Xu H. Jovanovic J.N. Buxbaum J.D. Wang R. Greengard P. Relkin N.R. S. G. J. Neurochem. 1998; 71: 1920-1925Crossref PubMed Scopus (106) Google Scholar). BACE1, on chromosome 11q23.2, and BACE2, on chromosome 21q22.3, exhibit 64% amino acid similarity (18Bennett B.D. Babu-Khan S. Loeloff R. Louis J.-C. Curran E. Citron M. Vassar R. J. Biol. Chem. 2000; 275: 20647-20651Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar), although they have distinct regulation and function (19Sun X. Wang Y. Qing H. Christensen M.A. Liu Y. Zhou W. Tong Y. Xiao C. Huang Y. Zhang S. Liu X. Song W. FASEB J. 2005; 19: 739-749Crossref PubMed Scopus (110) Google Scholar). BACE mRNA is expressed at low levels in most human peripheral tissues, yet unlike BACE1 (6Vassar R. Bennett B.D. Babu-Khan S. Kahn S. Mendiaz E.A. Denis P. Teplow D.B. Ross S. Amarante P. Loeloff R. Luo Y. Fisher S. Fuller J. Edenson S. Lile J. Jarosinski M.A. Biere A.L. Curran E. Burgess T. Louis J.-C. Collins F. Treanor J. Rogers G. Citron M. Science. 1999; 286: 735-741Crossref PubMed Scopus (3308) Google Scholar), human whole brain expresses very low or undetectable levels of BACE2 mRNA (18Bennett B.D. Babu-Khan S. Loeloff R. Louis J.-C. Curran E. Citron M. Vassar R. J. Biol. Chem. 2000; 275: 20647-20651Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar). BACE2 is not up-regulated in Bace1–/– mice (20Luo Y. Bolon B. Damore M.A. Fitzpatrick D. Liu H. Zhang J. Yan Q. Vassar R. Citron M. Neurobiol. Dis. 2003; 4: 81-88Crossref Scopus (153) Google Scholar) and functions more as an alternative α-secretase and as an antagonist of BACE1 (21Yan R. Munzner J.B. Shuck M.E. Bienkowski M.J. J. Biol. Chem. 2001; 276: 34019-34027Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar). BACE2 cleaves APP between Phe+19 and Phe+20 (1Cole S.L. Vassar R. Mol. Neurodegener. 2007; 2: 22Crossref PubMed Scopus (365) Google Scholar, 22Fluhrer R. Capell A. Westmeyer G. Willem M. Hartung B. Condron M.M. Teplow D.B. Haass C. Walter J. J. Neurochem. 2002; 81: 1011-1020Crossref PubMed Scopus (100) Google Scholar) to abolish Aβ production. Knowledge as to whether BACE1 has a vital function in vivo is of critical importance for the development of BACE1 inhibitors, and mouse models recapitulating key features of human AD pathology have been used to examine this. Notably, in Bace1–/– mouse brain, β-secretase activity is abolished. Although early data indicated that Bace1–/– mice lack any adverse phenotype (23Luo Y. Bolon B. Kahn S. Bennett B.D. Babu-Khan S. Denis P. Fan W. Kha H. Zhang J. Gong Y. Martin L. Louis J.-C. Yan Q. Richards W.G. Citron M. Vassar R. Nat. Neurosci. 2001; 4: 231-232Crossref PubMed Scopus (951) Google Scholar, 24Roberds S.L. Anderson J. Basi G. Bienkowski M.J. Branstetter D.G. Chen K.S. Freedman S.B. Frigon N.L. Games D. Hu K. Johnson-Wood K. Kappenman K.E. Kawabe T.T. Kola I. Kuehn R. Lee M. Liu W. Motter R. Nichols N.F. Power M. Robertson D.W. Schenk D. Schoor M. Shopp G.M. Shuck M.E. Sinha S. Svensson K.A. Tatsuno G. Tintrup H. Wijsman J. Wright S. McConlogue L. Hum. Mol. Genet. 2001; 10: 1317-1324Crossref PubMed Google Scholar), suggesting that BACE1 absence is well tolerated in vivo, more recent studies have identified specific Bace1–/–-associated phenotypes (discussed below). Further research is required to determine what such data mean for the clinical use of BACE1 inhibitors in the future. Fibrillar and soluble oligomeric Aβ forms (25Kuo Y.M. Emmerling M.R. Vigo-Pelfrey C. Kasunic T.C. Kirkpatrick J.B. Murdoch G.H. Ball M.J. Roher A.E. J. Biol. Chem. 1996; 271: 4077-4081Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar) accumulate in AD brain. In contrast to wild-type mice, Tg mice overexpressing APP with the FAD Swedish mutation (Tg2576) (26Hsiao K. Chapman P. Nilsen S. Eckman C. Harigaya Y. Younkin S. Yang F. Cole G. Science. 1996; 274: 99-103Crossref PubMed Scopus (3700) Google Scholar) produce robust levels of brain Aβ and age-dependently develop brain Aβ plaques. Bace1–/–·Tg2576 bigenic mice lack all forms of brain Aβ, APPsβ, and C99 compared with Bace1+/–·Tg2576 or Bace1+/+·Tg2576 mice (23Luo Y. Bolon B. Kahn S. Bennett B.D. Babu-Khan S. Denis P. Fan W. Kha H. Zhang J. Gong Y. Martin L. Louis J.-C. Yan Q. Richards W.G. Citron M. Vassar R. Nat. Neurosci. 2001; 4: 231-232Crossref PubMed Scopus (951) Google Scholar). Bace1–/–·Tg2576 animals fail to develop amyloid plaques (20Luo Y. Bolon B. Damore M.A. Fitzpatrick D. Liu H. Zhang J. Yan Q. Vassar R. Citron M. Neurobiol. Dis. 2003; 4: 81-88Crossref Scopus (153) Google Scholar), and similar findings were observed in another Bace1-deficient APP Tg model (27Laird F.M. Cai H. Savonenko A.V. Farah M.H. He K. Melnikova T. Wen H. Chiang H.C. Xu G. Koliatsos V.E. Borchelt D.R. Price D.L. Lee H.K. Wong P.C. J. Neurosci. 2005; 25: 11693-11709Crossref PubMed Scopus (454) Google Scholar), unequivocally proving that BACE1 is essential for amyloid formation and is the major β-secretase responsible for brain Aβ generation. To analyze the contribution of soluble Aβ to memory dysfunction, young pre-plaque Tg2576 mice, which develop memory impairments, were examined (28Ohno M. Sametsky E.A. Younkin L.H. Oakley H. Younkin S.G. Citron M. Vassar R. Disterhoft J.F. Neuron. 2004; 41: 27-33Abstract Full Text Full Text PDF PubMed Scopus (459) Google Scholar). Memory deficits did not develop in Aβ-deficient Bace1–/–·Tg2576 bigenic mice, whereas Aβ-overproducing Tg2576 monogenics exhibited florid deficits. These data provide direct evidence for the amyloid hypothesis in vivo and indicate that soluble Aβ is responsible for at least some aspects of AD-related memory deficits. Compared with single Tg models, APP/PS1 double Tg mice show accelerated Aβ accumulation and AD-associated memory deficits and have been used to investigate the consequences of BACE1 ablation on established amyloid pathology. Bace1 deletion abolished Aβ pathology and prevented specific memory deficits common to APP/PS1 Tg mice (27Laird F.M. Cai H. Savonenko A.V. Farah M.H. He K. Melnikova T. Wen H. Chiang H.C. Xu G. Koliatsos V.E. Borchelt D.R. Price D.L. Lee H.K. Wong P.C. J. Neurosci. 2005; 25: 11693-11709Crossref PubMed Scopus (454) Google Scholar, 29Oakley H. Cole S.L. Logan S. Maus E. Shao P. Craft J. Guillozet-Bongaarts A. Ohno M. Disterhoft J. Van Eldik L. Berry R. Vassar R. J. Neurosci. 2006; 26: 10129-10140Crossref PubMed Scopus (2003) Google Scholar, 30Ohno M. Chang L. Tseng W. Oakley H. Citron M. Klein W.L. Vassar R. Disterhoft J.F. Eur. J. Neurosci. 2006; 23: 251-260Crossref PubMed Scopus (227) Google Scholar, 31Ohno M. Cole S.L. Yasvoina M. Zhao J. Citron M. Berry R. Disterhoft J.F. Vassar R. Neurobiol. Dis. 2007; 26: 134-145Crossref PubMed Scopus (245) Google Scholar). 5XFAD mice coexpressing APP and PS1 with five FAD mutations exhibited aggressive pathology, memory deficits, and, unusually, significant neuronal loss in AD-sensitive brain regions (29Oakley H. Cole S.L. Logan S. Maus E. Shao P. Craft J. Guillozet-Bongaarts A. Ohno M. Disterhoft J. Van Eldik L. Berry R. Vassar R. J. Neurosci. 2006; 26: 10129-10140Crossref PubMed Scopus (2003) Google Scholar). Notably, amyloid pathology, deficits in hippocampus-dependent learning, and neuronal loss observed in 5XFAD mice were all rescued in Bace1–/–/5XFAD mice (30Ohno M. Chang L. Tseng W. Oakley H. Citron M. Klein W.L. Vassar R. Disterhoft J.F. Eur. J. Neurosci. 2006; 23: 251-260Crossref PubMed Scopus (227) Google Scholar, 31Ohno M. Cole S.L. Yasvoina M. Zhao J. Citron M. Berry R. Disterhoft J.F. Vassar R. Neurobiol. Dis. 2007; 26: 134-145Crossref PubMed Scopus (245) Google Scholar). Thus, Aβ peptides are involved in age-associated cognitive impairments and appear to be ultimately responsible for neuronal death. However, BACE1 is required for specific hippocampal memory processes, and potential mechanism-based toxicities result from complete Bace1 inhibition (27Laird F.M. Cai H. Savonenko A.V. Farah M.H. He K. Melnikova T. Wen H. Chiang H.C. Xu G. Koliatsos V.E. Borchelt D.R. Price D.L. Lee H.K. Wong P.C. J. Neurosci. 2005; 25: 11693-11709Crossref PubMed Scopus (454) Google Scholar, 28Ohno M. Sametsky E.A. Younkin L.H. Oakley H. Younkin S.G. Citron M. Vassar R. Disterhoft J.F. Neuron. 2004; 41: 27-33Abstract Full Text Full Text PDF PubMed Scopus (459) Google Scholar, 30Ohno M. Chang L. Tseng W. Oakley H. Citron M. Klein W.L. Vassar R. Disterhoft J.F. Eur. J. Neurosci. 2006; 23: 251-260Crossref PubMed Scopus (227) Google Scholar). Bace1 deficiency might be associated with a higher mortality rate in early life (32Dominguez D. Tournoy J. Hartmann D. Huth T. Cryns K. Deforce S. Serneels L. Camacho I.E. Marjaux E. Craessaerts K. Roebroek A.J. Schwake M. D'Hooge R. Bach P. Kalinke U. Moechars D. Alzheimer C. Reiss K. Saftig P. De Strooper B. J. Biol. Chem. 2005; 280: 30797-30806Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar), and Bace1–/– mice exhibit an emotional phenotype (27Laird F.M. Cai H. Savonenko A.V. Farah M.H. He K. Melnikova T. Wen H. Chiang H.C. Xu G. Koliatsos V.E. Borchelt D.R. Price D.L. Lee H.K. Wong P.C. J. Neurosci. 2005; 25: 11693-11709Crossref PubMed Scopus (454) Google Scholar, 33Harrison S.M. Harper A.J. Hawkins J. Duddy G. Grau E. Pugh P.L. Winter P.H. Shilliam C.S. Hughes Z.A. Dawson L.A. Gonzalez M.I. Upton N. Pangalos M.N. Mol. Cell. Neurosci. 2003; 24: 646-655Crossref PubMed Scopus (138) Google Scholar), appearing hyperactive, with enhanced locomotion (27Laird F.M. Cai H. Savonenko A.V. Farah M.H. He K. Melnikova T. Wen H. Chiang H.C. Xu G. Koliatsos V.E. Borchelt D.R. Price D.L. Lee H.K. Wong P.C. J. Neurosci. 2005; 25: 11693-11709Crossref PubMed Scopus (454) Google Scholar, 32Dominguez D. Tournoy J. Hartmann D. Huth T. Cryns K. Deforce S. Serneels L. Camacho I.E. Marjaux E. Craessaerts K. Roebroek A.J. Schwake M. D'Hooge R. Bach P. Kalinke U. Moechars D. Alzheimer C. Reiss K. Saftig P. De Strooper B. J. Biol. Chem. 2005; 280: 30797-30806Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar). As it would be nearly impossible to completely suppress BACE1 activity in vivo therapeutically, understanding the consequences of partial Bace1 inactivation is critically important. Indeed, partial BACE1 inactivation may not affect normal learning and memory processes and appears beneficial in reducing Aβ-associated pathologies and cognitive deficits. Whether there are differences in the putative benefit of adjusting BACE1 levels during early versus later disease stages remains to be clarified (27Laird F.M. Cai H. Savonenko A.V. Farah M.H. He K. Melnikova T. Wen H. Chiang H.C. Xu G. Koliatsos V.E. Borchelt D.R. Price D.L. Lee H.K. Wong P.C. J. Neurosci. 2005; 25: 11693-11709Crossref PubMed Scopus (454) Google Scholar, 34Singer O. Marr R.A. Rockenstein E. Crews L. Coufal N.G. Gage F.H. Verma I.M. Masliah E. Nat. Neurosci. 2005; 8: 1343-1349Crossref PubMed Scopus (361) Google Scholar, 35McConlogue L. Buttini M. Anderson J.P. Brigham E.F. Chen K.S. Freedman S.B. Games D. Johnson-Wood K. Lee M. Zeller M. Liu W. Motter R. Sinha S. J. Biol. Chem. 2007; 282: 26326-26334Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar). BACE1 is a prime therapeutic drug target for AD treatment. Understanding the control of BACE1 expression and BACE1 cell biology may illuminate the normal role of BACE1, identify disease-associated mechanisms, and suggest approaches to inhibit BACE1 therapeutically. The BACE1 gene, spanning ∼30 kb and including nine exons, is a strong candidate gene for sporadic AD. Although findings indicate that polymorphisms in exon 5 of the BACE1 gene associate with AD (36Clarimon J. Bertranpetit J. Calafell F. Boada M. Tarraga L. Comas D. J. Neurol. 2003; 250: 956-961Crossref PubMed Scopus (39) Google Scholar), clear mechanisms that underlie such associations remain hard to identify. The BACE1 promoter contains multiple transcription factor-binding sites (including those for interferon-γ, peroxisome proliferator-activated receptor-γ, and hypoxia-inducible factor-1) that likely influence transcriptional activity (37Sambamurti K. Kinsey R. Maloney B. Ge Y.W. Lahiri D.K. FASEB J. 2004; 18: 1034-1036Crossref PubMed Scopus (156) Google Scholar). In the brain, glia significantly outnumber neurons, and although BACE1 is predominantly a neuronal protein, glia may produce significant amounts of BACE1 and Aβ during inflammation. As a strong inflammatory reaction is present in AD brain, even a slight increase in glial BACE1 expression might substantially impact cerebral Aβ generation and exacerbate AD pathology. Certain pro-inflammatory molecules can elevate astrocytic Bace1 expression (38Cho H.J. Kim S.K. Jin S.M. Hwang E.M. Kim Y.S. Huh K. Mook-Jung I. Glia. 2007; 55: 253-262Crossref PubMed Scopus (89) Google Scholar), and Bace1 levels appear to rise at sites of glial activation prior to plaque development (39Heneka M.T. Sastre M. Dumitrescu-Ozimek L. Dewachter I. Walter J. Klockgether T. Van Leuven F. J. Neuroinflamm. 2005; 2: 22Crossref PubMed Scopus (239) Google Scholar). Interestingly, long-term nonsteroidal anti-inflammatory drug use reduces AD risk, an effect that may be mediated in part by activation of peroxisome proliferator-activated receptor-γ and subsequent repression of BACE1 promoter activity (40Sastre M. Dewachter I. Rossner S. Bogdanovic N. Rosen E. Borghgraef P. Evert B.O. Dumitrescu-Ozimek L. Thal D.R. Landreth G. Walter J. Klockgether T. Van Leuven F. Heneka M.T. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 443-448Crossref PubMed Scopus (347) Google Scholar). Specific stressful events are AD risk factors and link to AD pathogenesis. Interestingly, TBI and cellular consequences of vascular disease (e.g. hypoxia, oxidative stress) can elevate BACE1 mRNA levels (1Cole S.L. Vassar R. Mol. Neurodegener. 2007; 2: 22Crossref PubMed Scopus (365) Google Scholar, 41Tong Y. Zhou W. Fung V. Christensen M.A. Qing H. Sun X. Song W. J. Neural Transm. 2005; 112: 455-469Crossref PubMed Scopus (197) Google Scholar, 42Sun X. He G. Qing H. Zhou W. Dobie F. Cai F. Staufenbiel M. Huang L.E. Song W. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 18727-18732Crossref PubMed Scopus (463) Google Scholar). Furthermore, hypoxia increases Aβ production via BACE1 activity up-regulation both in vitro and in vivo. BACE1 undergoes complex regulation. Following synthesis in the endoplasmic reticulum, immature pro-BACE1 is transported through the secretory pathway. In the Golgi, BACE1 is processed by a furin-like proprotein convertase to remove the propeptide domain, and complex glycosylation generates mature 70-kDa BACE1 (5Vassar R. J. Mol. Neurosci. 2004; 23: 105-114Crossref PubMed Scopus (303) Google Scholar, 43Haniu M. Denis P. Young Y. Mendiaz E.A. Fuller J. Hui J.O. Bennett B.D. Kahn S. Ross S. Burgess T. Katta V. Rogers G. Vassar R. Citron M. J. Biol. Chem. 2000; 275: 21099-21106Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar). Unusually, the propeptide domain does not suppress protease activity, and pro-BACE1 may cleave APP to generate a potentially toxic intracellular Aβ pool (1Cole S.L. Vassar R. Mol. Neurodegener. 2007; 2: 22Crossref PubMed Scopus (365) Google Scholar). Glycosylation affects protease activity, and palmitoylation of the BACE1 C-terminal tail could potentially influence its localization and/or trafficking. Although BACE1 is considered an integral membrane protein, a small fraction undergoes ectodomain shedding, which may increase amyloidogenic APP processing (1Cole S.L. Vassar R. Mol. Neurodegener. 2007; 2: 22Crossref PubMed Scopus (365) Google Scholar). BACE1 localizes to cholesterol-rich lipid rafts, and specific lipids stimulate BACE1 activity (44Riddell D.R. Christie G. Hussain I. Dingwall C. Curr. Biol. 2001; 11: 1288-1293Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar). Although BACE1 homodimers exhibit enhanced catalytic activity, the protease interacts with several other proteins (e.g. reticulon/Nogo proteins, SorLA/LR11) that modulate the BACE1-APP interaction and/or BACE1 activity (1Cole S.L. Vassar R. Mol. Neurodegener. 2007; 2: 22Crossref PubMed Scopus (365) Google Scholar). Such interactions may provide clues for the therapeutic strategies to inhibit BACE1. Signals, including the acid cluster-dileucine motif in the BACE1 C-terminal tail, control the trafficking and subcellular localization of the protease, and members of the GGA (Golgilocalized γ-ear-containing ADP-ribosylation factor-binding) protein family interact with BACE1 to regulate this process (discussed below) (45Tesco G. Koh Y.H. Kang E.L. Cameron A.N. Das S. Sena-Esteves M. Hiltunen M. Yang S.H. Zhong Z. Shen Y. Simpkins J.W. Tanzi R.E. Neuron. 2007; 54: 721-737Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar). BACE1 enzymatic activity resides in the Golgi, the trans-Golgi network, and endosomes. In vivo, BACE1 is transported down axons of the perforant pathway (46Sheng J.G. Price D.L. Koliatsos V.E. Exp. Neurol. 2003; 184: 1053-1057Crossref PubMed Scopus (49) Google Scholar, 47Lazarov O. Lee M. Peterson D.A. Sisodia S.S. J. Neurosci. 2002; 22: 9785-9793Crossref PubMed Google Scholar), and BACE1 co-localizes with presynaptic markers (48Zhao J. Fu Y. Yasvoina M. Shao P. Hitt B. O'Connor T. Logan S. Maus E. Citron M. Berry R. Binder L. Vassar R. J. Neurosci. 2007; 27: 3639-3649Crossref PubMed Scopus (307) Google Scholar). Although the subcellular site of Aβ generation in vivo is difficult to asses, data indicate that APP is metabolized into Aβ peptides that are released and deposited as amyloid plaques around nerve terminals. Indeed, axon terminals are likely major sites of Aβ production (46Sheng J.G. Price D.L. Koliatsos V.E. Exp. Neurol. 2003; 184: 1053-1057Crossref PubMed Scopus (49) Google Scholar, 47Lazarov O. Lee M. Peterson D.A. Sisodia S.S. J. Neurosci. 2002; 22: 9785-9793Crossref PubMed Google Scholar). Although BACE1 is relatively stable, with a half-life of ∼9 h, this protease is degraded by endoproteolysis, the lysosome, and the ubiquitin-proteasome pathway (1Cole S.L. Vassar R. Mol. Neurodegener. 2007; 2: 22Crossref PubMed Scopus (365) Google Scholar). BACE1 inhibitors should offer benefit for AD patients, and structural analysis of BACE1-inhibitor complexes has proved useful for drug development (49Hong L. Koelsch G. Lin X. Wu S. Terzyan S. Ghosh A.K. Zhang X.C. Tang J. Science. 2000; 290: 150-153Crossref PubMed Scopus (700) Google Scholar). The BACE1 active site is more open and less hydrophobic that that of other family members. Four hydrogen bonds from the catalytic aspartic acid residues and 10 additional hydrogen bonds from various active-site residues are made with the inhibitor. Data indicate that Arg296 and the hydrophobic pocket of the active site are important for binding substrate, and small molecules targeting these residues should inhibit cleavage by BACE1. Furthermore, the bound inhibitor 0M99-2, which has a Ki of 1.6 nm for BACE1, has an unusual kinked conformation; thus, mimicking this unique conformation may increase the selectivity of BACE1 inhibitors. Although much data exist on the development of peptidomimetic and non-peptidomimetic BACE1 inhibitors (50John V. Curr. Top. Med. Chem. 2006; 6: 569-578Crossref PubMed Scopus (58) Google Scholar), researchers have struggled to develop compounds with high potency for BACE1, good blood-brain barrier penetration, and the appropriate pharmacokinetic characteristics. Nevertheless, a number of pharmaceutical companies have advanced programs for BACE1 inhibitors, providing encouragement that such therapeutics will eventually be available in the clinic. As discussed previously, mechanism-based toxicities may result from complete BACE1 inhibition. BACE1 is critical for Aβ generation, and normal neural Aβ production indicates that the peptide has physiological function(s). Indeed, the complete absence of Aβ in Bace1–/– mice caused specific memory impairments, suggesting that Aβ is involved in normal memory (28Ohno M. Sametsky E.A. Younkin L.H. Oakley H. Younkin S.G. Citron M. Vassar R. Disterhoft J.F. Neuron. 2004; 41: 27-33Abstract Full Text Full Text PDF PubMed Scopus (459) Google Scholar), consistent with Aβ involvement in regular neuronal function (51Kamenetz F. Tomita T. Hsieh H. Seabrook G. Borchelt D. Iwatsubo T. Sisodia S. Malinow R. Neuron. 2003; 37: 925-937Abstract Full Text Full Text PDF PubMed Scopus (1285) Google Scholar). Although neuronal BACE1 cleaves a proportion of APP, in non-neuronal tissues, APP is cleaved predominantly by α-secretase. Indeed, several other putative BACE1 substrates exist (1Cole S.L. Vassar R. Mol. Neurodegener. 2007; 2: 22Crossref PubMed Scopus (365) Google Scholar), and physiological functions for BACE1 have recently begun to emerge. The identification of neuregulin-1 and the sodium channel β-subunit as BACE1 substrates implicates BACE1 function in myelination and neuronal activity, respectively (1Cole S.L. Vassar R. Mol. Neurodegener. 2007; 2: 22Crossref PubMed Scopus (365) Google Scholar, 52Willem M. Garratt A.N. Novak B. Citron M. Kaufmann S. Rittger A. De Strooper B. Saftig P. Birchmeier C. Haass C. Science. 2006; 314: 664-666Crossref PubMed Scopus (608) Google Scholar, 53Wong H.K. Sakurai T. Oyama F. Kaneko K. Wada K. Miyazaki H. Kurosawa M. De Strooper B. Saftig P. Nukina N. J. Biol. Chem. 2005; 280: 23009-23017Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar). Furthermore, many of these putative BACE1 substrates are involved in the response to stress and/or injury (1Cole S.L. Vassar R. Mol. Neurodegener. 2007; 2: 22Crossref PubMed Scopus (365) Google Scholar). Given that BACE1 levels are elevated under stressful conditions, indications are that BACE1 functions as a stress-response protein and that cleavage of specific BACE1 substrates facilitates recovery after acute stress/injury. It is also hypothesized that, during chronic stress/injury, elevated BACE1 levels become pathogenic and facilitate harmful amyloid formation (1Cole S.L. Vassar R. Mol. Neurodegener. 2007; 2: 22Crossref PubMed Scopus (365) Google Scholar). Excessive Aβ deposition occurs in AD. Although the cause(s) of this in sporadic cases remains unknown, increased BACE1 activity may play a role. FAD caused by the APP Swedish mutation, which enhances APP cleavage by BACE1, suggests that elevated BACE1 activity can lead to AD. Notably, BACE1 activity increases with age (54Fukumoto H. Rosene D.L. Moss M.B. Raju S. Hyman B.T. Irizarry M.C. Am. J. Pathol. 2004; 164: 719-725Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar), and elevated BACE1 levels and/or activity are observed in AD brain (1Cole S.L. Vassar R. Mol. Neurodegener. 2007; 2: 22Crossref PubMed Scopus (365) Google Scholar, 55Fukumoto H. Cheung B.S. Hyman B.T. Irizarry M.C. Arch. Neurol. 2002; 59: 1381-1389Crossref PubMed Scopus (599) Google Scholar, 56Holsinger R.M. McLean C.A. Beyreuther K. Masters C.L. Evin G. Ann. Neurol. 2002; 51: 783-786Crossref PubMed Scopus (494) Google Scholar, 57Li R. Lindholm K. Yang L.B. Yue X. Citron M. Yan R. Beach T. Sue L. Sabbagh M. Cai H. Wong P. Price D. Shen Y. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 3632-3637Crossref PubMed Scopus (445) Google Scholar). As aging is the biggest AD risk factor, AD might reflect an exaggeration of age-related changes in BACE1 activity. However, a number of other significant AD risk factors could also potentially impact BACE1 levels and/or activity (see below). To address whether the BACE1 elevation is passively or actively involved in disease progression, the BACE1 elevation in the presence (5XFAD mice) or absence (Tg2576 mice) of cell death was analyzed (48Zhao J. Fu Y. Yasvoina M. Shao P. Hitt B. O'Connor T. Logan S. Maus E. Citron M. Berry R. Binder L. Vassar R. J. Neurosci. 2007; 27: 3639-3649Crossref PubMed Scopus (307) Google Scholar). The BACE1 elevation correlated with amyloid pathology in both models and appeared to be more than a passive end product of advanced neurodegeneration. Although the sequence of events leading to increased Aβ42 deposition remains undetermined, BACE1 localization to presynaptic structures around Aβ plaques (48Zhao J. Fu Y. Yasvoina M. Shao P. Hitt B. O'Connor T. Logan S. Maus E. Citron M. Berry R. Binder L. Vassar R. J. Neurosci. 2007; 27: 3639-3649Crossref PubMed Scopus (307) Google Scholar) indicates a positive feedback loop, whereby Aβ42 deposition in AD leads to BACE1 elevation, which further increases Aβ42 production. BACE1 regulation occurs at both the transcriptional and post-transcriptional levels (1Cole S.L. Vassar R. Mol. Neurodegener. 2007; 2: 22Crossref PubMed Scopus (365) Google Scholar). Although AD etiology remains enigmatic, it is plausible that multiple triggers exist to cause AD. Notably, several significant AD risk factors, including aging, specific vascular conditions, and TBI, can be linked to alterations in BACE1 levels and/or activity. On a molecular level, it is the cellular changes associated with such conditions (e.g. hypoxia, oxidative stress, energy metabolism deficits, inflammation) that might cause BACE1 elevation. Whereas hypoxia, oxidative stress, inflammation, and TBI can affect Bace1 transcription, energy deficiency and metabolic stress appear to alter its translation (58Velliquette R.A. O'Connor T. Vassar R. J. Neurosci. 2005; 25: 10874-10883Crossref PubMed Scopus (211) Google Scholar). The microenvironment also impacts BACE1 activity, whereas BACE1 stability can be affected under ischemic conditions (1Cole S.L. Vassar R. Mol. Neurodegener. 2007; 2: 22Crossref PubMed Scopus (365) Google Scholar). Whereas these observations support an early role for elevated BACE1 in AD (48Zhao J. Fu Y. Yasvoina M. Shao P. Hitt B. O'Connor T. Logan S. Maus E. Citron M. Berry R. Binder L. Vassar R. J. Neurosci. 2007; 27: 3639-3649Crossref PubMed Scopus (307) Google Scholar), it is likely that multiple factors elevate BACE1 throughout disease progression. Neuronal loss is a key pathological feature of AD, and enhanced caspase activation is observed in AD brain. Apoptosis enhances neuronal Aβ levels, and data show that GGA3 is cleaved during apoptosis and that inhibition of GGA3 elevates BACE1 levels, revealing a connection between neurodegeneration and BACE1 elevation (45Tesco G. Koh Y.H. Kang E.L. Cameron A.N. Das S. Sena-Esteves M. Hiltunen M. Yang S.H. Zhong Z. Shen Y. Simpkins J.W. Tanzi R.E. Neuron. 2007; 54: 721-737Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar). Clearly, whether or not stressful conditions such as certain types of vascular disease or TBI actually initiate AD or deleteriously contribute during disease progression remains to be determined. Since its discovery almost a decade ago, our understanding of BACE1 has increased significantly. However, despite promising news of BACE1 inhibitor development, routine clinical use of such therapeutics for AD treatment has yet to become a reality. A combination of technical difficulties, the complexity of BACE1 biology, and multifarious disease pathogenesis has slowed AD drug development. Indeed, our understanding of BACE1 continues to evolve. Given recent data hinting at important physiological roles for BACE1 (and APP), it is clear that careful titration of BACE1 dosage will be required for effective safe treatment. In addition, it is likely that further understanding of the molecular mechanisms underlying BACE1 elevation in AD will enhance the development of novel therapies for AD treatment and shed light on the etiology of this devastating disease.

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