T r e n d si nCell & MolecularB i o l o g yVol. 11, 2016

How an APP gene mutation protects against
Alzheimer’s disease?
Saori Hata*, Ayano Kimura, Yuzuha Shiraki and Toshiharu Suzuki
Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences,
Hokkaido University, Kita 12-Nishi 6, Kita-ku, Sapporo 060-0812, Japan.
ABSTRACTIn familial Alzheimer’s disease (AD), many
pathogenic mutations have been reported for
amyloid-β precursor protein (APP) and presenilin
1 and 2 genes. However, only one protective
mutation has been reported for the APP gene, in
Icelanders. Although APP metabolism is closely
related to intracellular trafficking of APP and
APP-cleaving enzymes, the mechanism of thecausative gene mutations remains largely unclear.
The Icelandic A673T mutation of the APP geneprotects against AD, whereas the A673V mutation
at the same amino acid position is pathogenic.
APP A673T markedly decreases generation of
CTFβ/C99, which is produced in the amyloidogenic
cleavage of APP by β-site APP-cleaving enzyme 1(BACE1). This CTFβ/C99 is further cleaved by
γ-secretase to generate neurotoxic amyloid-β 1-40
(Aβ1-40) and Aβ1-42 peptides. Because BACE1
activity is increased in intracellular acidic
compartments, it has been suggested that APP
A673T may escape from this BACE1-dependentamyloidogenic pathway. However, we propose
a novel hypothesis that BACE1 preferentiallycleaves APP A673T at the β′- rather than the
β-site, generating an amino-terminally truncatedAβ11-XX. This alternative β′-site cleavage of APP
decreases the generation of Aβ1-XX forms, which
is how the A673T mutation of APP functions
protectively against AD. Similarly, APP A673V ispreferentially cleaved at the β-site rather than*Corresponding author: shata@pharm.hokudai.ac.jp

the β′-site. This increases the generation of CTFβ/
C99 and the subsequent Aβ1-XX forms, comparedwith wild-type APP, and is the mechanism
whereby APP A673V functions pathogenically.
The previous suggestion that the molecular andcellular mechanisms underpinning the protective
A673T mutation of APP occurred via decreased
amyloidogenic processing of APP has been
controversial. Our novel finding that the aminoacid sequence within the Aβ region alters aproperty of APP cleavage by BACE1 is likely,
rather than the conventional explanation that an
APP mutation induces intracellular trafficking of
APP into an amyloidogenic pathway.
KEYWORDS: Alzheimer’s disease, BACE1,
APP, intracellular trafficking
ABBREVIATIONS
AD, Alzheimer’s disease; APP, amyloid β-precursor
protein; Aβ, amyloid β; BACE1, β-site APPcleaving enzyme-1; CTF, C-terminal fragment of
APP truncated at the primary cleavage site.
INTRODUCTION
There are many mutations on the amyloid βprecursor protein (APP) and presenilin (PSEN)-1
and PSEN2 genes in familial Alzheimer’s disease(FAD) [1]. Almost all of these are pathogenic for
AD through the increased generation of amyloid-β(Aβ) peptides or the facilitated production of Aβ
species with a longer carboxy terminus, which
express more neurotoxicity and are generated
from APP cleavage by the aberrant activity of68
γ-secretase, including presenilin 1 or 2 (PS1/2)
harboring a FAD mutation. Because substrate APP
and all APP-cleaving enzymes are membraneproteins, Aβ generation is linked to the intracellulartransport of APP. Some causes of sporadic AD,
which does not harbor any causative mutations on
APP and PSEN genes, may be due to the alteredintracellular trafficking of APP and APP-cleaving
membrane-associated enzymes.
APP is a type I transmembrane protein, existingin several isoforms (APP770, APP751, and APP695)
that arise by alternative slicing of a single APP
gene. In the biosynthetic process of APP inneurons, APP is subject to N-glycosylation in theendoplasmic reticulum and O-glycosylation in the
Golgi [2]. The mature N- and O-glycosylated APP
is further phosphorylated in the cytoplasm andtransported to nerve terminals by kinesin-1 [3-7].
In the late secretary pathway, APP is subject toproteolytic cleavage; therefore, APP intracellulartransport and metabolism are closely related.
Alterations in intracellular trafficking of APP arethought to alter APP processing in terms of quality
or quantity or both, which is suggested from theindependent genome-wide association study ofpatients with AD, indicating that disease-related
single polymorphisms are found in genes for
endocytosis and membrane vesicular trafficking[8-11]. Intracellular transport of APP is largely
regulated in its short cytoplasmic region, whereinmany cytoplasmic proteins interact for regulating
intracellular trafficking of APP or membrane
microdomain localization [12-17]. Therefore, thefunctions of these cytoplasmic regulators may be
aberrant in sporadic AD.
In contrast to those for sporadic AD, mutations of
APP in familial AD are detected in extracellular
plus transmembrane domains covering the Aβ
region, and no mutations are observed in thecytoplasmic region, which is evolutionally highly
conserved in amino acid sequence. Thus, some of
the APP pathogenic mutations are available forcleavage by secretases. For example, the Swedish
mutation K670N/M671L facilitates β-site cleavage
by BACE1 to generate Aβ1-XX, and the London
mutation V717I alters γ-site cleavage by
γ-secretase to increase Aβ1-42 but not Aβ1-40 [18,19]. However, how a protective mutation locatedin the Aβ region affects the cleavage of APP byα-, β- and γ-secretases remains unknown.

Saori Hata et al.
Intracellular trafficking and metabolism of APP
Intracellular APP trafficking and metabolism aresummarized in figure 1, and the secretase cleavage
sites on APP are indicated in figure 2. In general,
APP is primarily cleaved by APP α-secretases
ADAM10 and ADAM17. This α-site cleavage of
APP occurs at the peptide bond between Lys687
and Leu688, cleaving the Aβ region of APP togenerate CTFα/C83. This APP cleavage largely
occurs in the plasma membrane. The resultant
CTFα/C83 is further cleaved by a γ-secretase
complex that includes PS1 or PS2 to generateamino-terminally truncated Aβ, Aβ17-XX, namedwith the p3 fragment. This p3 fragment ismetabolically labile and difficult to detect in
cerebrospinal fluid, even when large amounts ofthe p3 fragment are generated from APP in vivo.
Therefore, α-cleavage of APP does not generate
neurotoxic Aβ forms such as Aβ1-42; thus this APP
metabolism is considered the non-amyloidogenic
or amyloidolytic pathway. A small percent of
APP can escape this pathway and become subject
to endocytosis, entering an intracellular endosomal
pathway in which β-site APP-cleaving enzyme-1(BACE1) cleaves APP in the acidic environment,
largely at the β-site to generate CTFβ/C99. This
CTFβ/C99 is further cleaved by the γ-secretase
complex, as is CTFα/C83, to generate neurotoxic
Aβ1-XX. This metabolism is considered theamyloidogenic pathway of APP. Enhanced entry of
APP into the amyloidogenic pathway along withattenuated entry of APP into the non-amyloidogenic/
amyloidolytic pathway is a predominant cause of
AD pathogenesis [17, 20-22].
BACE1 cleaves APP at several sites
The majority of the BACE1 cleavage of APP
occurs between Met671 and Asp672 (β-site
cleavage) to generate CTFβ/C99. However, BACE1
also cleaves APP at Tyr681 and Glu682 (β′-site
cleavage) to generate an N-terminally truncatedAβ [23, 24], and at Leu705 and Met706 (β′′-site
cleavage) to generate a C-terminally truncated Aβ[25] (Figure 2). A pioneer study using primarycultured neurons reported that murine APP
generates predominantly N-terminally truncatedAβ11-xx lacking ten amino acids in the amino
terminus [26]. It was concluded that murine BACE1
preferentially cleaves APP at the β′-site, generating
C89/CTFβ′, rather than at the β-site to generateMechanism of APP mutation protection in Alzheimer’s disease

69

Figure 1. Schematic overview of APP intracellular transport and metabolism in neurons. The nonamyloidogenic or amyloidolytic pathway of APP. Mature APP with N- and O-glycosaccharides is subject toanterograde transport by kinesin-1 motor and reaches the plasma membrane. Large segments of APP are
amyloidolytically cleaved by α-secretases (α) to generate sAPPα and CTFα/C83. CTFα/C83 is further cleaved by
γ-secretase (γ) to secrete the p3 fragment along with the intracellular release of AICDα from the membrane. This is
the non-amyloidogenic pathway (A). Some APP is subject to endocytosis and enters endosomal pathway in which
acidic compartment BACE1 (β) is active to cleave APP at the β- or β'-site to generate CTFβ/C99 and CTFβ'/C89
along with sAPPβs. These CTFβs are further cleaved by γ-secretase to produce Aβ1-xx and Aβ11-xx. The Aβs are
secreted by exocytosis together with sAPPβs; therefore, this is the amyloidogenic pathway (B). Secreted Aβ forms
neurotoxic oligomers to impair neuronal synapses.

Figure 2. Amino acid sequences in the Aβ region of human and mouse APP. Amino acids at three positions in
the Aβ region of mouse APP (lower) differ from those of human APP (upper). Based on the amino acid numberingof the human APP770 isoform, Arg676, Tyr681, and His684 of human APP are Gly676, Phe681, and Arg684,
respectively, in mouse APP. Icelandic Ala673Thr and Leuven Glu682Lys mutations of human APP are also
indicated. Cleavage sites of APP by β-secretase (BACE1) as well as the peptide bonds between Met671 and Asp672(β-site), between Tyr681 and Glu682 (β′-site), and between Leu705 and Met706 (β′′-site) are shown with an αsecretase cleavage site (α-site) and typical γ-secretase cleavage sites (γ-sites).

70
C99/CTFβ. Although APP subject to cleavage by
BACE1 in the intracellular compartment may
differ in mice and humans, the completely conserved
amino acid sequence of the APP cytoplasmic
region among various animals, including a fish,
conflicts with the idea of a species difference [27].
A recent report shows that mouse APP is cleaved
at the β′-site rather than at the β-site in human ormouse neuroblastoma cells, whereas human APP
is predominantly cleaved at the β-site in bothhuman and mouse neuroblastoma cells [28]. Thisfinding indicates that the difference in APP
cleavage by BACE1 in humans and mouse is notdependent on the species specificity of BACE1,
nor is it due to events in different intracellularcompartments, at least when the amino acidsubstitutions are located within the amino-terminal
half of the Aβ region (Figure 2).

Saori Hata et al.
There are three amino acid alterations within theamino-terminal half of the Aβ region in the mouse
APP compared with the amino acid sequence ofhuman APP. The differences are observed at
position 676 (Arg in human is Gly in mouse;
R676G), Y681F, and H684R. When His at position
684 of human APP is changed to the mouse Arg,
the human APP harboring H684R shows mousetype cleavage of APP preferentially at the β′-site,rather than the human-type cleavage predominantat the β-site (Figure 3). In other words, a singleamino acid substitution in human APP can increaseβ′-site cleavage compared with β-site cleavage.
The amino acid sequence-dependent preference of
APP cleavage by BACE1, that is, a preferential
choice of either β- or β′-site cleavage of APP by
BACE1, is confirmed by an in vitro assay [28].
These data clearly indicate that the preference of

Figure 3. Amino acid position 684 plays an important role in determining whether BACE1 will cleave at theβ- or β′-site of human APP. Human APP, mouse APP, and the human APP harboring the H684R (mouse type)amino acid substitution were expressed in mouse neuroblastoma N2a cells. Secreted Aβ forms were analyzed byimmunoprecipitation–MS. (A) Representative MS spectra of Aβ in the medium. (B) The Aβ11-40/Aβ1-40 ratio wasdetermined (n = 5; ± S.E.). The statistical significance of the differences between the human APP and the mouse
APP and human APP H684R was determined using Dunnett’s multiple comparisons test (***p < 0.001).

Mechanism of APP mutation protection in Alzheimer’s diseaseβ- or β′-site cleavage of APP by BACE1 depends
on the amino acid sequence of the Aβ region
rather than the species specificity of BACE1 orcleavage in different intracellular compartments[28].
Pathogenic and protective mutations within
the amino-terminal half of the Aβ region
affect the selection of β- or β′-site cleavageof APP by BACE1First, we focus on the Icelandic protective (A673T)
and pathogenic (A673V) mutations, which arelocated close to the β-cleavage site, and the
Leuven pathogenic mutation (E682K) within the
β′-cleavage site, which cuts a peptide bond
between Y681 and E682 [29-31] (Figure 2). The
Leuven E682K mutation increases Aβ1-XX secretionand enhances production of CTFβ/C99 in cells[30]. Interestingly, APP harboring the Leuven
E682K mutation shows markedly fewer β′cleaved products (Aβ11-XX) along with a decreasein CTFβ′/C89 (Figure 4), indicating that the Leuven
E682K mutation attenuates the β′-cleavage of
APP, as compared with the increased β-site
cleavage of APP, to generate Aβ1-XX. This is thereason that the Leuven E682K mutation functions
pathogenically.

71

Next, we look at the APP with a mutation at
position 673, which is located two amino acids
from the β-cleavage site on the carboxy-terminalside (Figure 2). APP harboring A673V shows
markedly increased cleavage at the β-site to
generate CTFβ/C99, whereas the presence of
A673T significantly decreases the production of
CTFβ/C99 (Figure 5A). Furthermore, APP harboring
A673V decreases the generation of Aβ11-XX,
whereas APP harboring A673T increases Aβ11-XX
production. Taken together, the relative ratio of
Aβ11-XX to Aβ1-XX (Aβ11-XX/Aβ1-XX) significantly
decreases with the pathogenic A673V mutation,
but markedly increases with the protective A673T
mutation (Figure 5B) along with decreased
secretion of Aβ1-40 and Aβ1-42 (Figure 5C). This
result indicates that the molecular mechanism forthe protective mutation at position 673 of APP isdue to the enhancement of APP β′-site cleavage
by BACE1, along with the attenuation of β-site
cleavage by the same enzyme [28]. For the aminoacid substitution at position 673 of APP, it isreasonable to think that the preference of APP βor β′-site cleavage by BACE1 is determined by
the amino acid sequence of the Aβ region rather
than a species difference in BACE1 or in the different
intracellular compartments where APP is cleaved.

Figure 4. Attenuated β'-site cleavage by BACE1 of the human APP harboring the pathogenic Leuven E682K
mutation. Human APP wild-type (WT) and APP E682K were expressed in N2a cells. (A) CTFβ/C99, CTFβ'/C89,
and CTFα/C83 in cell lysates and Aβ1-40 in media were analyzed by Western blotting followed byimmunoprecipitation. (B) Aβ forms in the medium were also analyzed by immunoprecipitation–MS to detect
Aβ11-XX forms.

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Saori Hata et al.

Figure 5. Enhanced β'-cleavage by BACE1 of the human APP harboring the protective Icelandic A673T
mutation. Human wild-type (WT) APP as well as pathogenic (A673V) and protective (A673T) APP mutations wereexpressed in N2a cells. (A) CTFβ/C99, CTFβ'/C89, and CTFα/C83 in cell lysates were analyzed by Western
blotting. (B) Aβ forms in the medium were analyzed by immunoprecipitation–MS to detect Aβ11-XX forms, and theAβ11-40/Aβ1-40 ratios were determined (n = 5; ± S.E.). (C) Aβ1-40 and Aβ1-42 in the medium were also quantified bysELISA. The statistical significance of the differences between WT APP and APP A673V and APP A673T wasdetermined using Dunnett’s multiple comparisons test (*p < 0.05; ***p < 0.001).

The neurotoxicity of the amino-terminallytruncated Aβ forms, including Aβ11-40 and/or Aβ11-42,
is controversial [32, 33]. However, compared with
Aβ1-40 and Aβ1-42, the truncated forms are
metabolically labile in vivo and in vitro [28].
Murine primary cultured neurons generate Aβ11-XX
predominantly from endogenous APP [26, 28];
however, the amount of Aβ11-XX in cerebrospinal
fluid is lower than that of Aβ1-XX. Even if theAβ11-XX forms show weaker neuronal toxicity, themolecules are subject to faster degradation or
clearance in vivo, diminishing their neuronaltoxicity.
CONCLUDING REMARKSThe protective effect of the Icelandic APP A673T
mutation against AD is largely due to enhanced
cleavage of APP at the β′-site along with theattenuated cleavage of APP at the β-site. This β′site cleavage of APP generates amino-terminallytruncated Aβ11-XX forms, followed by γ-secretasecleavage of CTFβ′/C89. This conclusion may
conflict with an expectation that the mutations
alter the intracellular trafficking of APP. However,in the case of familial AD with mutations in theamino-terminal half of the Aβ region of APP, thechoice for β- or β′-site cleavage of APP by
BACE1 is largely dependent on the amino acidsequence of substrate APP. In sporadic AD
without any mutations of the APP and PSEN
genes, alterations in the intracellular transport of
APP and APP-cleaving enzymes may play animportant role in the pathogenesis, including
enhanced Aβ generation and/or facilitated productionof more neurotoxic Aβ forms such as Aβ1-42.
Furthermore, the Aβ11-XX forms generated by β′cleavage are metabolically more labile than the
Aβ1-XX forms in living neurons in vivo and may besubject to faster clearance prior to neurotoxic
oligomerization, even if Aβ11-XX still possesses
some neurotoxicity.

Mechanism of APP mutation protection in Alzheimer’s disease
ACKNOWLEDGMENTS
This work was supported in part by Grants-in-aid
for Scientific Research 15K18854 (S. H.), and262930110 and 16K14690 (T. S.) from the Ministryof Education, Culture, Sports, Science, andTechnology of Japan.
CONFLICT OF INTEREST STATEMENT
There are no conflicts of interest.
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