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J. Biol. Chem., Vol. 275, Issue 27, 20647-20651, July 7, 2000

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Expression Analysis of BACE2 in Brain and Peripheral Tissues^*

Brian D. Bennett, Safura Babu-Khan, Richard Loeloff, Jean-Claude Louis, Eileen Curran, Martin Citron, and Robert Vassar

From Amgen, Inc., Thousand Oaks, California 91320-1799

Received for publication, March 29, 2000

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Beta-site amyloid precursor protein cleaving enzyme (BACE) is a novel transmembrane aspartic protease that possesses all the known characteristics of the -secretase involved in Alzheimer's disease (Vassar, 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., and Citron, M. (1999) Science 286, 735-741). We have analyzed the sequence and expression pattern of a BACE homolog termed BACE2. BACE and BACE2 are unique among aspartic proteases in that they possess a carboxyl-terminal extension with a predicted transmembrane region and together they define a new family. Northern analysis reveals that BACE2 mRNA is expressed at low levels in most human peripheral tissues and at higher levels in colon, kidney, pancreas, placenta, prostate, stomach, and trachea. Human adult and fetal whole brain and most adult brain subregions express very low or undetectable levels of BACE2 mRNA. In addition, in situ hybridization of adult rat brain shows that BACE2 mRNA is expressed at very low levels in most brain regions. The very low or undetectable levels of BACE2 mRNA in the brain are not consistent with the expression pattern predicted for -secretase.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Amyloid plaques, composed of the 4-kDa -amyloid peptide (A),¹ are hallmark lesions found in Alzheimer's disease brain (1). Evidence suggests that A plays a central role in the pathogenesis of Alzheimer's disease (2). Two major forms of A differing at the carboxyl terminus are generated, A40 and A42, and overproduction of the longer peptide is highly correlated with early-onset familial Alzheimer's disease (3).

A is formed by proteolysis of amyloid precursor protein (APP), a large type-I transmembrane protein (4). The protease -secretase initiates A formation by cleaving at the amino terminus of the A domain to generate the secreted APPs ectodomain and the membrane-bound carboxyl-terminal fragment C99 (see Fig. 1 of Ref. 5). A second protease called -secretase then cleaves C99 to form the carboxyl terminus of the mature A peptide. In a nonamyloidogenic pathway, APP is processed by the protease -secretase, which cleaves within the A domain to produce the soluble APPs ectodomain and the membrane-bound C83 fragment. C83 is cleaved by -secretase to produce the nontoxic p3 fragment. The - and -secretase cleavages of APP are both required for A formation, and the inhibition of either or both of these secretases is a prime therapeutic goal for the treatment of Alzheimer's disease.

Until recently, the identities of the secretases had been elusive. The metalloproteases TACE and ADAM 10 both appear to be involved in -secretase processing of APP (6) (7). Presenilin is required for -secretase activity (8, 9), and it has been suggested that presenilin 1 itself is -secretase (10). However, direct demonstration that presenilin 1 possesses -secretase activity is so far lacking. We and others have recently identified a novel transmembrane aspartic protease, beta-site APP cleaving enzyme (BACE), that exhibits all the known properties of -secretase (5, 11-14). The BACE polypeptide sequence contains two active site motifs (D(T/S)G(T/S)) that are characteristic of aspartic proteases, and BACE appears most closely related to the pepsin aspartic protease family (for review, see Ref. 15). However, BACE differs from members of the pepsin family in that it possesses a carboxyl-terminal extension of ~80 amino acids that contains a predicted transmembrane region and a short cytosolic tail. Thus, BACE is predicted to be a type-1 transmembrane protein with the active site in the lumen and represents the first reported example of a transmembrane aspartic protease.

Recently, we and others have identified a homolog of BACE termed BACE2 (or Asp1; GenBank^TM accession number AF204944) by searching expressed sequence tag data bases (12, 16). The BACE2 gene resides on chromosome 21 in the obligate Down's syndrome region at 21q22.3 (16). This region contains the APP gene and is triplicated in the genomes of Down's syndrome patients, suggesting that the additional copy of the APP gene is responsible for the Alzheimer's-like dementia and the amyloid plaques that invariably develop in Down's syndrome patients (17). The high amino acid similarity of BACE and BACE2, together with the localization of the BACE2 gene within the obligate Down's syndrome region, suggest that BACE2 may be a -secretase candidate.

Here, we present a detailed comparison of the polypeptide sequences of BACE and BACE2 with each other and with members of the pepsin family. Our analysis indicates that BACE and BACE2 are members of a novel family of transmembrane aspartic proteases. We have analyzed the expression of BACE2 mRNA in human peripheral tissues and brain by Northern blot and in rat brain by in situ hybridization. The levels of BACE2 mRNA are very low or undetectable in the brain and are not consistent with the predicted expression pattern for -secretase.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Alignments of BACE and BACE2 with the Pepsin Family-- The amino acid sequence alignments of BACE and BACE2 versus the pepsin family (see Fig. 1) were generated using the Clustal W alignment algorithm of the MacVector sequence analysis software (Oxford Molecular Group, Inc., Campbell, CA). The percentages of amino acid similarities were calculated using the percentage homology algorithm of MacVector. The phylogenetic tree (see Fig. 2) was constructed using the GrowTree algorithm of the Wisconsin Sequence Analysis Package (Genetics Computer Group, Madison, WI).

Northern Analysis-- Human multiple tissue, endocrine, brain region, and fetal Northern blots (CLONTECH; Palo Alto, CA) were hybridized for 2 h at 65 °C in Express Hybe (CLONTECH) with ³²P-radiolabled human BACE2 cDNA BstXI fragment (nucleotides +230 to +1232). Blots were washed once at room temperature in 2× SSC, and then washed two to three times at 60 °C in 0.2× SSC, 0.1% SDS. Washed blots were exposed to a PhosphorImager screen for 48 h and were visualized with a Storm 860 PhosphorImager (Molecular Dynamics; Sunnyvale, CA). Blots were then stripped for 30 min in 0.1× SSC, 1% SDS, 100 °C and rehybridized with a radiolabeled control probe for human -actin (CLONTECH).

In Situ Hybridization Analysis-- In situ hybridizations were performed using 10-µm sections through fresh frozen brain tissue obtained from adult Harlan Sprague-Dawley rats. Antisense riboprobes labeled with [³⁵S]UTP and [³⁵S]CTP were generated from rat BACE cDNA BglII-KpnI fragment (nucleotides +815 to +1593) and BACE2 cDNA PvuII-NotI fragment (nucleotides +1027 to +1820). Hybridization and wash conditions were as described previously (18).

	RESULTS

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Sequence Analysis of BACE and BACE2-- The BACE2 polypeptide is 518 amino acids, has a putative amino-terminal signal sequence from residues 1 to 20, and is predicted to have a propeptide domain immediately following the signal sequence (15, 19) (Fig. 1). BACE2 has two aspartic protease active site motifs of the sequence D(T/S)G(T/S) at amino acids 109-112 and 300-303, positions that are conserved with BACE. BACE2 also has two predicted N-linked glycosylation sites and six luminal cysteine residues that are at positions closely conserved with BACE. Therefore, BACE and BACE2 are each predicted to form up to three intramolecular disulfide bonds and may possess very similar tertiary structures. Finally, like BACE, BACE2 has a carboxyl-terminal extension of ~80 residues with a single predicted transmembrane domain and a short cytosolic tail. These characteristics indicate BACE2 is a type-1 transmembrane protein with the aspartic protease active site placed within the lumen.

View larger version (104K): [in this window] [in a new window]   Fig. 1.   Alignment of BACE and BACE2 polypeptide sequences with those of representative pepsin family members (cathepsin E, cathepsin D, renin, and pepsinogen A). Letters refer to the single letter amino acid code. Letters boxed and shaded in dark gray denote identical amino acids, whereas letters boxed and shaded in light gray denote similar amino acids. Dashes represent gaps in the polypeptide sequences. Red Cs represent luminal cysteine residues capable of forming intramolecular disulfide bonds. Red Ns are predicted N-linked glycosylation sites. The red Ys at position 160 represent conserved tyrosine residues important for catalytic activity or substrate specificity (30). Amino- and carboxyl-terminal active site motifs are identified by brackets above the sequence, and the predicted transmembrane domains in BACE and BACE2 are indicated by the overline.

BACE shares 64% amino acid similarity with BACE2. In contrast, BACE or BACE2 shares ~40-44% amino acid similarity with individual pepsin family members, whereas the pepsins typically share higher levels of amino acid similarity among themselves (52-69%; see Fig. 2 legend). The carboxyl-terminal extension of BACE and BACE2 is not present in other aspartic proteases (Fig. 1). Although two of the luminal cysteine residues (at positions 317 and 369 in Fig. 1) of BACE and BACE2 have positions that are conserved with the pepsin family, the other four cysteines are at considerably divergent positions with respect to those of the pepsins. In contrast, the positions of all six cysteine residues are exactly conserved among members within the pepsin family (Fig. 1). Taken together, these sequence characteristics indicate that BACE and BACE2 define a novel family of transmembrane aspartic proteases, a point further illustrated by phylogenetic analysis (Fig. 2).

View larger version (10K): [in this window] [in a new window]   Fig. 2.   Phylogenetic tree showing pairwise relationships of BACE and BACE2 with representative members of the pepsins and retropepsins. Relationships were generated using the GrowTree algorithm (Wisconsin Sequence Analysis Package) and are based on percentage amino acid similarities. Representative percentage similarities are: BACE to BACE2, 64%; BACE to pepsinogen A, 43%; BACE to cathepsin E, 43%; BACE to renin, 41%; BACE to cathepsin D, 40%; pepsinogen A to cathepsin E, 69%; pepsinogen A to cathepsin D, 61%; pepsinogen A to renin, 52%. The retropepsins are retroviral aspartic proteases from Moloney murine leukemia virus (MMLV asp), human immunodeficiency virus (HIV asp), and Rous sarcoma virus (RSV asp) (for review, see Ref. 15). The retroviral proteases are homodimeric enzymes and evolutionarily are more ancient as compared with the single polypeptide chain eukaryotic aspartic proteases.

Expression Analysis of BACE2-- -Secretase expression is predicted to be higher in neurons of the brain than in peripheral cells or glia (20, 21). Therefore, we determined whether the expression pattern of BACE2 mRNA is consistent with that expected of -secretase. Northern blot analysis of mRNAs extracted from different human peripheral tissues and brain reveals two BACE2 transcripts of approximately 2.0 and 2.6 kilobases (Fig. 3). BACE2 mRNA is expressed at low levels in most adult tissues but appears to be higher in colon, kidney, pancreas, placenta, prostate, stomach, and trachea. Adult whole brain and most brain subregions express very low or undetectable levels of BACE2 mRNA, with the exception of medulla and spinal cord, which express slightly higher levels (Fig. 3). Human fetal peripheral tissues express relatively low levels of BACE2 mRNA, whereas fetal brain expresses little or no BACE2 mRNA.

View larger version (32K): [in this window] [in a new window]   Fig. 3.   Northern analyses of mRNAs isolated from human multiple tissues, endocrine tissues, brain subregions, and fetal tissues for BACE2 mRNA. Northern blots were hybridized with radiolabeled BACE2 cDNA BstXI fragment probe (nucleotides +230 to +1232), washed under stringent conditions, and visualized by PhosphorImager analysis (upper panels). Blots were stripped and rehybridized with radiolabeled -actin control probe (bottom panels). Tissue sources for mRNAs are indicated above each lane. Molecular weight markers (in kilobases) are indicated at the left of the first panel.

To determine the cellular distribution of BACE2 mRNA in the brain, we performed in situ hybridization of adult rat brain sections with an antisense RNA probe complementary to rat BACE2 cDNA (Fig. 4). At low magnification, BACE2 mRNA is expressed at very low levels throughout most regions of the brain, except in a limited number of brain nuclei such as the ventromedial hypothalamus (VMH) and the mammilary body (MM) and in some neurons of the spinal cord (Fig. 4B). In contrast, BACE mRNA is expressed at relatively high levels throughout most regions of the brain as compared with that of BACE2 mRNA (compare Figs. 4A and 4B; also see Fig. 3, D-F, in Ref. 5). Similar to BACE, BACE2 mRNA signal is observed over neurons, whereas little or no expression is observed in glia (not shown). However, unlike BACE, the very low or undetectable levels of BACE2 mRNA in most regions of human and rat brain are not consistent with the expression pattern expected for -secretase.

View larger version (38K): [in this window] [in a new window]   Fig. 4.   In situ hybridization of adult rat brain for BACE and BACE2 mRNAs: low magnification images of parasagittal sections. Serial sections were hybridized with radiolabeled antisense RNA probes complementary to BACE (A) or BACE2 (B) mRNAs. Sections were washed under high stringency conditions and exposed to x-ray film for 7 days. Both BACE and BACE2 probes were approximately 800 bases long and were radiolabeled with relatively the same specific activity. Therefore, based on relative signal strengths, the level of BACE mRNA appears significantly higher than BACE2 mRNA throughout most regions of the brain, with the exception of a limited number of nuclei, including MM and VMH, some spinal cord neurons, and ependymal cells lining the surface of the brain. CA3, CA3 region of hippocampus; DG, dentate gyrus; MM, mammilary body; NTS, nucleus of the solitary tract; Pir, piriform cortex; Pn, pontine nuclei; Tu, olfactory tubercle; VMH, ventromedial hypothalamic nucleus.

	DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

BACE and BACE2 Define a Novel Family of Aspartic Proteases-- BACE and BACE2 are the first reported examples of transmembrane aspartic proteases, defining a new family. No other aspartic proteases identified to date possess a carboxyl-terminal extension with a predicted transmembrane region. Three yeast aspartic proteases, Yapsins 1-3, associate with the membrane via a glycosyl-phosphatidylinositol (GPI) anchor (22-24); however, no mammalian GPI-linked aspartic proteases have been identified. The function of the Yapsins are unknown, although several studies have demonstrated that the Yapsins are capable of cleaving at the -secretase site of APP in yeast (24-26). Based on this observation, Olsen et al. (1999) have proposed that the Yapsins may be involved in the conversion of membrane-bound precursors to secreted proteins. Membrane attachment through the Yapsin GPI anchor may facilitate the processing of membrane-bound precursor proteins by concentrating the enzyme at the lipid bilayer. In a similar fashion, the association of BACE and BACE2 with the membrane via the carboxyl-terminal transmembrane domain may increase the efficiency or specificity of cleavage of membrane-bound substrates. This suggestion is consistent with the identification of APP as a substrate of BACE, given that APP is a type I transmembrane precursor protein that is processed into secreted forms. Alternatively, membrane attachment may be important for the intracellular localization or compartmentalization of BACE and BACE2. At present, no BACE substrates other than APP have been identified, nor are the substrates of BACE2 known. The identification of BACE and BACE2 substrates will be important for understanding the potential role of membrane association and the biological functions of BACE and BACE2.

In addition to the carboxyl-terminal extension, BACE and BACE2 differ from the pepsins in other notable respects. For example, the carboxyl-terminal active site motif of BACE and BACE2 is DSGTT rather than the more common DTGTS of the pepsin family (Fig. 1). Moreover, only two of six luminal cysteine residues in BACE and BACE2 occupy positions that are conserved with those of the pepsins, whereas the positions of all six cysteines are invariant among members of the pepsin family (Fig. 1). Therefore, the intramolecular disulfide bond structure of BACE and BACE2 may be very different from that of the pepsins. Finally, there appears to be no relationship between the N-linked glycosylation sites of BACE and BACE2 with those of the pepsins. Taken together, these sequence differences suggest that BACE and BACE2 may have atypical properties (e.g. substrate specificities and/or catalytic activities) as compared with the properties of pepsin family members.

Eukaryotic aspartic proteases are single chain molecules consisting of two highly homologous lobes connected by a flexible hinge region, which suggests that this enzyme class evolved through gene duplication and fusion (for review, see Ref. 27). It follows that the primordial aspartic proteases may have been homodimers of single lobed polypeptides, and the subsequent discovery of the homodimeric retroviral proteases, including human immunodeficiency virus protease, confirmed this prediction. Evolutionarily, BACE and BACE2 form a separate family distinct from the pepsin family and the family of retroviral aspartic proteases (Fig. 2). However, as expected, BACE and BACE2 are more closely related to the pepsins than to the more ancient retroviral proteases.

The distribution of BACE and BACE2 mRNAs in peripheral tissues and brain does not suggest an obvious function for either BACE or BACE2. BACE mRNA is expressed at high levels in brain and pancreas, and in the brain BACE mRNA is expressed by neurons but not glia (5). BACE2 mRNA is expressed at very low or undetectable levels in most regions of the human and rat brain, with the exception of neurons in a limited number of brain nuclei, including VMH and MM, and some spinal cord neurons (Figs. 3 and 4). Peripherally, BACE2 mRNA is primarily expressed in colon, kidney, pancreas, placenta, prostate, stomach, and trachea (Fig. 3). Given the expression of BACE2 mRNA in particular brain nuclei, it is tempting to speculate that BACE2 is involved in proteolytic processing of substrates such as prohormones or proneuropeptides, which are important for the function of specific neurotransmitter systems. In this context, it appears that at least one aspartic protease, pro-opiomelanocortin-converting enzyme, is potentially involved in prohormone processing in the brain (28, 29).

Is BACE2 a Likely -Secretase Candidate?-- The BACE2 gene is located within the obligate Down's syndrome region on chromosome 21 (16). This observation, together with the high amino acid sequence similarity of BACE and BACE2, suggested the possibility that BACE2 is a -secretase candidate. -Secretase activity is higher in neurons than in peripheral cells or glia, indicating higher neuronal expression of -secretase (20, 21). The very low levels of BACE2 mRNA that we observe in the majority of brain regions in both human and rat are not consistent with the expression pattern expected for -secretase. In contrast, BACE mRNA is expressed at relatively higher levels in neurons throughout most of the brain and follows the predicted -secretase expression pattern (Fig. 4) (5).

To date, we and four other groups have reported that BACE exhibits the properties of the -secretase, whereas no study thus far has provided evidence that BACE2 possess -secretase activity (5, 11-14). Moreover, Yan et al. (1999) have shown that BACE2 antisense inhibition does not significantly reduce the level of A production in cells. In contrast, BACE antisense oligonucleotides dramatically inhibit -secretase activity (5, 12). In our expression cloning experiments, we have screened ~860,000 and ~750,000 independent clones from cDNA libraries made from mRNA of both HEK293 and SK-N-SH cell lines, respectively, and we have never isolated BACE2 cDNAs even though BACE2 mRNA is expressed in these cells. By comparison, we identified a total of 14 BACE cDNA clones from the same screens.² Finally, we have performed preliminary BACE2 transfection experiments and observe that BACE2 overexpression does not appear to increase the production of A in cells.³. Taken together, the results thus far suggest that BACE2 is unlikely to be a major -secretase in comparison to BACE, at least in the brain. However, the ultimate resolution of this issue will require determining whether BACE2 can cleave APP at the -secretase site and, if so, with what kinetics relative to BACE.

	ACKNOWLEDGEMENTS

We thank Desiree Olivares for help with figure preparation.

	FOOTNOTES

^* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EMBL Data Bank with accession number(s) AF204944.

To whom correspondence should be addressed: Amgen, Inc., One Amgen Center Drive, M/S 29-2-B, Thousand Oaks, CA 91320-1799. Tel.: 805-447-1289; Fax: 805-480-1347; E-mail: rvassar@amgen.com.

Published, JBC Papers in Press, April 3, 2000, DOI 10.1074/jbc.M002688200

² B. D. Bennett, S. Babu-Khan, M. Citron, and R. Vassar, unpublished.

³ S. Babu-Khan, B. D. Bennett, R. Vassar, and M. Citron, unpublished.

	ABBREVIATIONS

The abbreviations used are: A, -amyloid peptide; APP, amyloid precursor protein; BACE, beta-site APP cleaving enzyme; VMH, ventromedial hypothalamus; MM, mammilary body; GPI, glycosyl-phospatidylinositol.

	REFERENCES

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