Tài liệu Báo cáo khoa học: Upregulation of the a-secretase ADAM10 – risk or reason for hope? docx

REVIEW ARTICLE
Upregulation of the a-secretase ADAM10 – risk or reason
for hope?
Kristina Endres and Falk Fahrenholz
Department of Psychiatry and Psychotherapy, Clinical Research Group, Johannes Gutenberg-University, Mainz, Germany
Identification of ADAM10 as a
functional a-secretase
A disintegrin and metalloproteinase 10 (ADAM10)
originally came into focus in genetical and biochemical
research as a peptide sequence purified from bovine
brain myelin membrane preparations [1], and was
referred to as MADM (i.e. mammalian disintegrin-me-
talloprotease). Accidentally, this metalloproteinase was
identified via an artifact resulting from in vitro studies:
it has been described as a proteinase for the cytosolic
myelin basic protein [2], which is a rather unphysiolog-
ical substrate for the type I transmembrane enzyme
ADAM10. Further studies revealed that ADAM10 is
expressed in a wide variety of tissues either in Bos
taurus [3] and, more interestingly, in distinct areas of
the human brain [4,5] and peripheral structures [6,7].
Striking similarity concerning the inhibitory profile of
ADAM10 [8] with the putative a-secretase [9] sug-
gested a more physiological role for its enzymatic
activity: overexpression of the ADAM10 cDNA in
HEK293 cells first identified its function as an amyloid
precursor protein (APP) cleaving a-secretase [8], which
subsequently was verified in vivo. Alzheimer’s disease
(AD) model mice, which were crossbred with
ADAM10 transgenic mice, revealed a strongly attenu-
ated plaque pathology and an enhanced production

of the a-secretase derived soluble cleavage product
APPs-a [10]. Furthermore, these mice had an increased
learning and memory potential [10], which might
correlate with the observed enhanced cholinergic and
Keywords
alpha-secretase; amyloid precursor protein;
Alzheimer’s disease; domain structure;
neuroprotection; shedding; synaptogenesis;
TACE
Correspondence
K. Endres and F. Fahrenholz, Department of
Psychiatry and Psychotherapy, Clinical
Research Group, Johannes Gutenberg-
University, 55131 Mainz, Germany
Fax: + 49 6131 176690
Tel: + 49 6131 172133
E-mail:
uni-mainz.de;
(Received 4 November 2009, revised 10
December 2009, accepted 6 January 2010)
doi:10.1111/j.1742-4658.2010.07566.x
A decade ago, a disintegrin and metalloproteinase 10 (ADAM10) was iden-
tified as an a-secretase and as a key proteinase in the processing of the amy-
loid precursor protein. Accordingly, the important role that it plays in
Alzheimer’s disease was manifested. Animal models with an overexpression
of ADAM10 revealed a beneficial profile of the metalloproteinase with
respect to learning and memory, plaque load and synaptogenesis. Therefore,
ADAM10 presents a worthwhile target with respect to the treatment of a
neurodegenerative disease such as Morbus Alzheimer. Initially, ADAM10
was suggested to be an enzyme, shaping the extracellular matrix by cleavage

of collagen type IV, or to be a tumour necrosis factor a convertase. In a rel-
atively short time, a wide variety of additional substrates (with amyloid pre-
cursor protein probably being the most prominent) has been identified and
the search is still ongoing. Hence, any side effects concerning the therapeutic
enhancement of ADAM10 a-secretase activity have to be considered. The
present review summarizes our knowledge about the structure and function
of ADAM10 and highlights the opportunities for enhancing the expression
and ⁄ or activity of the a-secretase as a therapeutic target.
Abbreviations
5-HT4, serotonin 5-hydroxytryptamine; AD, Alzheimer’s disease; ADAM, a disintegrin and metalloproteinase; APP, amyloid precursor protein;
Ab, b-amyloid protein; GPCR, G protein-coupled receptor; GPI, glycosylphosphatidylinositol; PACAP, pituitary adenylate cyclase-activating
peptide; PKC, protein kinase C; SH3, Src homology 3; TACE, tumour necrosis factor a cleaving enzyme.
FEBS Journal 277 (2010) 1585–1596 ª 2010 The Authors Journal compilation ª 2010 FEBS 1585
glutamatergic synaptogenesis [11]. By contrast, mice
with a dominant negative mutant of ADAM10 had
lowered amounts of APPs-a, accompanied by an
enhanced amount of plaques [10] and learning deficien-
cies in the Morris water maze test [12]. In summary,
what began with a fallacious observation ended up
with the discovery of an enzyme that might have impli-
cations for a therapeutic approach in AD [13–15].
Protein structure and gene
organization of ADAM10
The enzyme ADAM10 belongs to the subgroup of
metzincins within the zinc proteinases family. The typi-
cal multidomain structure of ADAM10 as a type I
integral transmembrane protein consists of a prodo-
main, a catalytical domain with a conserved zinc bind-
ing sequence, a cysteine-rich disintegrin-like domain, a
transmembrane domain and a rather short cytoplasmic

domain (Fig. 1).
The nascent protein itself is not functional and is
produced as a zymogene. After cleavage of the signal-
ling sequence, ADAM10 enters the secretory pathway
to be processed and thereby activated by the propro-
tein convertases furin or PC7 [16]. This constitutive
processing has been demonstrated for the prodomains
of several ADAMs [17–19]. Regarding ADAM10, the
prodomain was revealed to exhibit a dual function: the
separately expressed prodomain was capable of inacti-
vating endogenous ADAM10 in cell culture experi-
ments but overexpressed ADAM10 without its
prodomain was inactive [16]. By contrast, coexpression
of the prodomain in trans rescued the activity of the
deletion mutant of ADAM10 without the intramolecu-
lar prodomain [16]. In addition, the recombinant mur-
ine prodomain purified from Escherichia coli acts as a
potent and selective competitive inhibitor in experi-
ments performed in vitro [20]. This implicates that the
prodomain of ADAM10 acts not only as a transient
inhibitor, but also as an internal chaperone in the mat-
uration of the enzyme. Accordingly, the viral delivery
of furin into the brain of AD model mice increased
a-secretase activity and reduced b-amyloid protein
(Ab) production in infected brain regions [21], demon-
strating the in vivo relevance of the removal of the
prodomain of ADAM10. Recently, by reciprocal coim-
munoprecipitation, tetraspanin 12 was identified as an
interaction partner for ADAM10 that enhances a-sec-
retase shedding of APP, probably by regulating matu-

ration of the prodomain of ADAM10 [22].
The catalytical domain of ADAM10 contains a
typical zinc-binding consensus motif (HEXGHXX
GXXHD; Fig. 1) and the point mutation E384A,
which compromises this motif, leads to a substantial
decrease in APPs-a secretion in HEK cells and in mice
[10,23]. Glycosylation sites in the catalytic and disinte-
grin domain contain high-mannose as well as complex-
type N-glycans, and a mutation at the N-glycosylation
site N439 increased ADAM10s susceptibility to proteo-
lytical degradation [24].
Although the removal of the disintegrin domain of
ADAM10 did not grossly affect shedding of APP in
cell culture experiments [23], cleavage of some sub-
strate molecules is likely to be influenced by noncata-
lytical domains. For example, epidermal growth factor
3
708
|
PKLPPPKPLPGTLKRRRPPQPIQQPQRQRPR

pat.7


pat.4

bipartite
1
2
4

5
210
|
RKKR
383
|
HEVGHNFGSPHD
Fig. 1. Domain structure of human ADAM10. ADAM10 is com-
posed of five different domains: the prodomain (1) has bifunctional
properties as an intramolecular chaperone and as an inhibitor of the
catalytic function in the zymogene. By detaching the prodomain via
proprotein convertase cleavage (recognition motif shown), the cata-
lytic domain with the conserved zinc binding motiv (2) becomes
activated. A mutation of the glutamate residue at position 384
(highlighted) into an alanine leads to a dominant-negative mutant of
the enzyme. The cystein-rich disintegrin domain (3) is followed by a
transmembrane region (4). In the intracellular space, a short cyto-
plasmic domain protrudes (5), which contains important sequence
motives for protein localization (SH3 motifs highlighted) [28,29]. In
addition, nuclear localization sequences have been assumed
because the ADAM10 intracellular domain was found to translocate
to the nucleus [41,79]: PSORTII analysis indicates two pattern 4,
one pattern 7 and one bipartite nuclear localization sequence
(underlined).
Upregulation of ADAM10 K. Endres and F. Fahrenholz
1586 FEBS Journal 277 (2010) 1585–1596 ª 2010 The Authors Journal compilation ª 2010 FEBS
cleavage is at least partially impaired in ADAM10
) ⁄ )
cells overexpressing a cytoplasmic domain deletion
mutant of ADAM10 [25]. In accordance with this find-

ing, the cytoplasmic domain of ADAM10 contains an
IQ consensus binding site for calmodulin that afflicts
maturation of the proteinase [25]. Additionally,
ADAM10 has been shown to be activated by a
calcium ionophore and the calmodulin inhibitor triflu-
oroperazine [26,27]. The cytoplasmic domain of
ADAM10 furthermore contains two proline-rich puta-
tive Src homology 3 (SH3) binding domains, from
which the juxtamembrane domain affects basolateral
localization of ADAM10 in epithelial cells [28]. In neu-
rones, the SH3 binding domains direct ADAM10 via
binding to synapse-associated protein-97 to the post-
synaptic membrane [29].
In 1997, the gene locus for ADAM10 was matched
to chromosome 15 in humans (15q21.3-q23) and chro-
mosome 9 in mice [30,31]. Subsequently, it took
8 years to achieve further gene structure analysis and
potential identification of transcription factor binding
sites [32]. We now know that the human, mouse and
rat genes, which comprise  160 kb, include a highly
homologous sequence within the first 500 bp upstream
of either translation initiation site. Deletion analysis
defined nucleotides )508 to )300 bp as the human
core promoter. This promoter was also identified as a
TATA-less promoter with functional binding sites for
Sp1, USF and retinoic acid receptors [32,33]. The func-
tional promoter of  2 kb displayed activity in various
human cell lines, such as HEK293, HepG2 or
SH-SY5Y, which reflects the ubiquitous basal expres-
sion of the endogenous ADAM10.

Single nucleotide polymorphism analyses of the pro-
moter region of 104 AD patients versus control
patients (n = 84) did not lead to significant statistical
differences [32]. In addition, an independent recent
study, genotyping 27 single nucleotide polymorphisms
covering the entire gene for ADAM10 in a larger
cohort of patients (n = 438 AD; n = 290 control),
revealed no single-marker or haplotypic association
with the disease [34]. This indicated that the gene for
ADAM10 probably does not constitute a major risk
with regard to AD. Nevertheless, a very recent study
of 1439 DNAs from 436 multiplex AD families yielded
significant evidence for an association of AD with the
metalloproteinase with respect to two mutations:
Q170H and R181G [35]. Both mutations are located
close to the cysteine switch within the prodomain and
the proprotein convertase recognition site (Fig. 1),
which explains their strong impact on enzyme func-
tionality: Chinese hamster ovary cells stably overex-
pressing mutated ADAM10 showed strongly
attenuated a-secretase activity [35]. Although both
mutations are rare (segregation in seven AD families
out of 1004) and are only partially penetrant, these
results give support to the hypothesis that the human
gene for ADAM10 plays a role in the aetiology of
AD.
ADAM10 and tumour necrosis factor a
(TACE): the ill-matched couple
Three members of the ADAM family have been shown
to act as a-secretase [8,36,37]: ADAM9, ADAM10 and

ADAM17 (TACE). Overexpression of ADAM9 has
been reported to increase the basal and protein kinase
C (PKC) dependent APPs-a release [36], although the
purified enzyme failed to cleave a synthetic peptide at
the major a-secretase cleavage-site [17]. Additionally,
mice lacking ADAM9 revealed no differences in the
production of the a-secretase cleavage product of APP
[38]. The impact of ADAM9 promoter polymorphism
on sporadic AD, which has been described recently
[39], might therefore rely on a more indirect mecha-
nism: ADAM9 has been shown to proteolytically pro-
cess ADAM10 [40–42]. By contrast to ADAM9,
ADAM10 was found to have constitutive and regu-
lated a-secretase activity as well as many other proper-
ties expected for the a-secretase [8,10]. Moreover,
in situ hybridization analysis in human cortical neuro-
nes provided evidence for the coexpression of APP
with ADAM10, suggesting that this proteinase is most
likely the physiologically relevant a-secretase [4].
Finally, experiments performed with ADAM17
(TACE)-deficient cells indicated a participation of
TACE in the regulated, PKC-stimulated [37,43] and
the constitutive a-secretase pathway [44,45]. To our
knowledge, there are no published reports about
TACE acting as an in vivo APP-sheddase in transgenic
mice, although TACE-positive neurones are found to
colocalize with amyloid plaques in AD brains support-
ing its role as an a-secretase [46].
On the basis of these results, it can be concluded
that ADAM10 and TACE are the major sheddases

that balance the b-site amyloid precursor protein cleav-
ing enzyme-driven generation of Ab peptides. This is
consistent with the close structural relationship of both
metalloproteinases: although TACE of human origin
has  30% amino acid identity relative to bovine
ADAM10, it only shows  15% identity with
ADAM9 [47]. Additionally, only those two ADAMs
lack the RX(6)DLPEFa(9)b(1) integrin binding motif,
which is contained in the other members of the pro-
teinase family [48]. Nevertheless, there are significant
differences between ADAM10 and TACE that
K. Endres and F. Fahrenholz Upregulation of ADAM10
FEBS Journal 277 (2010) 1585–1596 ª 2010 The Authors Journal compilation ª 2010 FEBS 1587
probably allow a specific modulation of one of them
for therapeutic approaches. TACE not only differs in
the consensus sequence of its disintegrin domain from
ADAM10 or by including a Crambin-like domain [47],
but also in its regulation. Several studies have
described the treatment of cellular cultures with a dis-
tinct outcome for either TACE or ADAM10 activity:
for example, incubation with phorbol 12-myristate 13-
acetate increased the turnover of TACE in Jurkat cells
[49] and diminished the amount of mature TACE in
HEK293 as well as in SH-SY5Y cells [45]. Interest-
ingly, these cell lines did not show altered amounts of
ADAM10, suggesting a significant difference in the cel-
lular stability of the mature enzyme forms after treat-
ment with 4b-phorbol 12-myristate 13-acetate [45]. In
addition, ADAM10 and TACE vary in their reaction
to cellular differentiation by retinoic acid [50,51] and

active site determinants of substrate recognition [52].
ADAM10: not particular about its
substrates?
For the enzyme ADAM10, more than 40 substrates
have been identified that belong to three different classes
of membrane bound proteins [53]. Most of them are
type I transmembrane proteins such as APP [8], APP-
like protein 2 [50] or the receptor for glycosylation end
products [54,55]. Type II transmembrane proteins such
as the apoptosis-inducing Fas ligand [56,57] or Bri2 [58]
have also been reported to be shed by ADAM10. Addi-
tionally, at least three glycosylphosphatidylinositol
(GPI)-anchored proteins are candidate substrates for
ADAM10: the metastasis-associated protein C4.4A was
characterized by a proteome technique as a substrate of
ADAM10 [59]. Furthermore, the GPI-anchored neuro-
nal guidance molecule ephrin A5 is cleaved by
ADAM10 upon binding to its receptor EphA3, leading
to termination of the receptor–ligand interaction [60].
Third, from cell culture experiments, the prion protein
PrP
c
was suggested to be processed by ADAM10 [40,61]
and the abundance of the PrP cleavage product C1 was
associated with mature ADAM10 within a small set of
human cerebral cortex samples [62]. However, in vivo
overexpression of ADAM10 in mice reduced all cellular
prion protein species instead of generating enhanced
amounts of cleavage products [63].
The substrates of ADAM10 show a

wide range of cellular function
ADAM10 cleaves proteins that affect cell migration
(N-cadherin [64]; transmembrane chemokines [65]) and
cell proliferation (CXCL16 [66–68]). It also sheds pro-
teins with functions in either the immune system (low
affinity immunoglobulin E receptor [69,70]; vascular
endothelial cadherin [71]) or in cell signalling (Delta
[72]; Notch [73]). Most effects, provoked by ADAM10
shedding activity, have been associated with the huge
N-terminal ectodomains of the substrates of ADAM10
that are released into the intercellular fluid upon cleav-
age. However, some effects have clearly been matched
to the intracellular domains of the substrates: ectodo-
main shedding by ADAM10 is followed by regulated
intramembrane proteolysis. After cleavage of the
Notch receptor by ADAM10, c-secretase releases a
small intracellular part of Notch, which then translo-
cates to the nucleus and acts as a transcription factor
[74–76]. With regard to Bri2, the ADAM10-derived
cleavage is followed by signal peptide peptidase-like
protease activity, also resulting in the release of a small
Bri2 fragment into the cell body [58].
In summary, ADAM10 has a repertoire of different
protein substrates hampering the development of ther-
apeutic strategies that target specifically APP by
ADAM10. However, not all substrates described as
being cleaved in the in vitro system have been con-
firmed in vivo. Mutagenesis experiments have depicted
at least three residues in the S1¢ pocket of ADAM10
that strongly influence substrate specificity and also

limit the number of substrates [52]. Additional interac-
tions of ADAM10 noncatalytical domains with the
substrate or with adaptor molecules, as previously
described for the recognition of ephrins [60], also
appear to be important for targeting ADAM10 to a
distinct substrate in the physiological context.
Regulators of ADAM10 expression and
catalytical activity
Because of the above-mentioned involvement of
ADAM10 in a wide range of cellular functions, it is
obvious to consider its therapeutic potential in various
diseases such as cancer or AD. ADAM10 has been
shown to cleave tumour-associated substrates such as
MICA [77] or C4.4A [59] and to be linked to progres-
sion of certain cancer types such as prostate or breast
cancer [78–80]. Furthermore, it plays a role in metasta-
sis of human colon cancer cells [81]. Therefore, the
inhibition of ADAM10 might be helpful in cancer
treatment in certain contexts [82]. By contrast,
ADAM10 overexpression or activation in the brain
might be beneficial for the treatment of neurodegenera-
tive diseases, in particular AD: this progressive disor-
der of the brain goes ahead with the loss of synaptic
junctions and neuronal cells. For ADAM10 overex-
pressing mice, it has been demonstrated that cortical
Upregulation of ADAM10 K. Endres and F. Fahrenholz
1588 FEBS Journal 277 (2010) 1585–1596 ª 2010 The Authors Journal compilation ª 2010 FEBS
synaptogenesis is enhanced [11], long-term potentiation
deficiency in AD model mice is rescued [10] and learn-
ing, as well as memory, is positively influenced by

ADAM10 [83]. Studies with the dominant negative
form of ADAM10 in a mouse model of AD revealed
that the enzymatic activity of ADAM10 is required to
counteract cognitive deficits [12]. In addition, axonal
guidance is conveyed by the metalloproteinase, as has
been shown for retinal and peripheral axons [84,85],
and ADAM10 regulates axon withdrawal by ephrin
cleavage [60,86].
It remains a matter of controversy as to whether
there is a substantial decline of neuronal ADAM10 in
ageing or in the pathological context: healthy, ageing
human fibroblasts did not reveal lowered amounts of
ADAM10 during senescence [87], although its specific
cleavage product APPs-a was decreased. Another
study demonstrated ADAM10 mRNA to be upregulat-
ed in cases of presenile dementia but to be downregu-
lated in the brain of AD patients [4]. A decrease for
ADAM10 and APPs-a was confirmed in human plate-
lets [88,89] as well as for APPs-a in the cerebrospinal
fluid of AD patients. Additionally, a recent study
revealed that colocalization of ADAM10 and one of
its potential regulators (i.e. nardilysin) is reduced in
AD compared to healthy aged brains [90].
With regard to these reports and to studies with
ADAM10 overexpression in a mouse AD model [10],
in principal, the enhancement of ADAM10 activity
and ⁄ or amount in the patient’s brain appears to be
valuable. How can this be achieved? Different
approaches appear to be promising, such as interfering
with the transcription ⁄ translation of ADAM10 or reg-

ulating its enzymatic capacity by influencing the mem-
brane physiology or via protein interactions (Fig. 2).
A first point of intervention within the biosynthetic
pathway of ADAM10 is provided by directly interfer-
ing with the expression of the gene for ADAM10: the
promoter region of the gene for ADAM10 has been
characterized in detail [32] and in silico analyses have
provided a multitude of transcription factor binding
sites. One of the putative binding sites for retinoic acid
receptors located at )302 and )203 bp has been dem-
onstrated to be functional by electrophoretic mobility
shift assay, promoter assays and APPs-a secretion in
human neuronal cells [32,50]. In addition, acitretin,
which is an accredited synthetic retinoid drug, lowered
Ab peptide generation in AD model mice and
enhanced APPs-a secretion [33]. Acitretin, which is
already used in the long-term treatment of patients suf-
fering from skin diseases withdraws all-trans retinoic
acid from its cellular retinoic acid binding protein and
makes it available for activating the corresponding
nuclear receptors. In the case of ADAM10 regulation,
cell culture studies with a variety of ligands for nuclear
receptors narrowed the receptors involved down
to a nonpermissive retinoic acid receptor–retinoid
X receptor heterodimer [33].
Another approach is offered by targeting the nascent
ADAM10 molecules during maturation within the cell.
Enhancement of the expression of a proprotein conver-
tase such as furin will increase ADAM10 maturation
Fig. 2. ADAM10 bears several points of vantage for its regulation.

For regulating the amount or catalytic activity of ADAM10, different
approaches such as interfering with membrane composition or pro-
teolytical processing of the proteinase itself are conceivable. In
addition, protein interaction partners such as TIMPs, tetraspanins
or reversion-inducing cysteine-rich protein with Kazal motifs (RECK)
modify the enzymatic property of ADAM10. GPCR-mediated cellular
signalling has been described for PACAP binding to PAC1 and tran-
scription factor based induction of gene expression (e.g. via retinoid
acid receptors) also contributes to ADAM10 activity within the cell.
Electrophoretic mobility shift assay experiments and application of
nuclear receptor ligands to the human neuroblastoma cell line
SH-SY5Y have identified important functional binding sites for non-
permissive retinoic acid receptor–retinoid X receptor heterodimers
at posititons )302 and ⁄ or )203 bp [32,33]. These can be directly
stimulated by addition of all-trans retinoic acid (atRA) or indirectly
by acitretin, liberating all-trans retinoic acid from cellular retinoic
acid binding protein. Pathways or molecules positively influencing
ADAM10 activity are indicated by a ‘+’ symbol, those with an
inhibitory effect by a ‘)’ symbol and those with an unknown
outcome by a ‘?’ symbol.
K. Endres and F. Fahrenholz Upregulation of ADAM10
FEBS Journal 277 (2010) 1585–1596 ª 2010 The Authors Journal compilation ª 2010 FEBS 1589
and a-secretase activity [21]. A further cleavage of
ADAM10 has been described in close proximity to
and within its transmembrane domain [40–42]. This is
a result of metalloproteinases ADAM9 and 15 acting
on ADAM10 to release a soluble sADAM10 from the
cell surface. sADAM10 was incapable of shedding cell-
associated amyloid precursor protein [42], whereas it
cleaved a synthetic peptide substrate [41,42] and

endogenous prion protein in cell culture experiments
[40]. Because it is still unclear whether soluble
ADAM10 and the transmembrane variant cleave the
same substrates and whether they have the same cata-
lytic properties in vivo, this type of regulation has to
be elucidated further. Acetylcholine esterase inhibitors,
which are already used in the symptomatic treatment
of AD, enhance the transport of ADAM10 to the cell
surface and the non-amylodogenic cleavage of APP
[91,92].
ADAM10 has also been shown to be regulated by
the lipid composition of the plasma membrane. While
cholesterol depletion enhanced its activity [93,94],
targeting ADAM10 via an artificial GPI-anchor to
cholesterol-rich domains inhibited its enzymatic func-
tion [95]. In human cells, the amount and activity of
ADAM10 was enhanced by statin application [93].
However, the outcomes of clinical trials with the chol-
esterol lowering statins are not unambiguous: several
studies have reported a protective effect of statins
against AD [96,97], although this could not be con-
firmed in others [98,99]. Nevertheless, in the prospec-
tive, population-based Rotterdam study comprising
 7000 participants, the use of statins was associated
with a lower risk of AD [100], preserving the hope of
a therapeutic value for statins in AD therapy. Further
evidence for lipids acting as modulators of a-secretase
activity is provided by a study demonstrating that type
III secretory phospholipase A and arachidonic acid
increased APPs-a production most likely by enhancing

substrate availability at the cell surface [101].
Another approach to activate ADAM10 could rest on
noncovalent protein interaction partners of ADAM10.
The tissue inhibitors of metalloproteinases 1 and 3 have
been shown to inhibit ADAM10 in vitro [102] and
the reversion-inducing cysteine-rich protein with Kazal
motifs also comprises a physiological ADAM10 inhibi-
tor [103]. By contrast, for the N-arginine dibasic
convertase (nardilysin), an activating property for
ADAM10-mediated APP a-secretase cleavage and
tumour necrosis factor a cleavage has been reported
[104,105]. The same holds true for the tetraspanins:
tetraspanin 12 increases maturation and activity of
ADAM10 [22] and ADAM10 has been suggested as a
component of the ‘tetraspanin web’ [106], which also
scaffolds heterotrimeric G protein-coupled receptors
(GPCRs) [107]. For the development of drugs interact-
ing with those proteins and thereby modulating
ADAM10 activity, further studies are necessary.
An appropriate strategy for targeting ADAM10 is
presented by directly stimulating the ADAM10 activity
by ligands of GPCRs. For example, the GPCR ligands
LPA and bombesin induced ADAM10-driven epider-
mal growth factor receptor transactivation [108] and
shedding of the thyrotropin receptor by ADAM10 was
mediated by its ligand thyrotropin [109]. At least in
cell culture, the a-secretase cleavage of APP is induc-
ible by the neuropeptide pituitary adenylate cyclase-
activating peptide (PACAP), which involves signalling
via mitogen-activated protein kinase and phosphatidyl-

inositol 3-kinase [110]. These results are of special
interest because the neuropeptide PACAP offers the
opportunity of locally activating the PAC1 receptor
and a-secretase in the brain. This also holds true for
the serotonin 5-hydroxytryptamine (5-HT4) receptor,
which increases memory and learning: the 5-HT4(e)
receptor isoform induced a-secretase activity by the
cAMP-regulated guanine exchange factor Epac and
the small GTPase Rac [111,112]. This recently led to
synthesis and evaluation of novel 5-HT4-agonists; two
of them increased APPs-a production in the cortex
and hippocampus of mice and exhibited neuroprotec-
tive properties [113].
Therefore, GPCR ligands offer an interesting oppor-
tunity in regulating ADAM10, even if the signalling
pathways have not yet been elucidated in every detail.
Another signalling pathway regulating ADAM10 activ-
ity is connected with the PKC: in various in vitro stud-
ies, it has been demonstrated that PKC or certain
isoforms of PKC stimulate the a-secretase [114–116]
(for the role of PKC in AD, see [117]) and this has
been confirmed in AD model mice (e.g. bryostatin 1)
[118].
ADAM10 as target for AD therapy:
lessons learned from transgenic mice
In summary, several independent strategies for enhanc-
ing the amount or the catalytic activity of ADAM10
have been performed or are conceivable. The crucial
question remaining is whether there are side effects
connected with enhanced ADAM10 activity in the

brain or in peripheral structures. ADAM10 mono-
transgenic mice with a permanent neuronal overexpres-
sion of ADAM10 to various extent were inconspicuous
in morphology, breeding and in daily handling [10].
This indicates that, by overexpression of ADAM10 in
the brain, the homeostasis of the entire organism is
Upregulation of ADAM10 K. Endres and F. Fahrenholz
1590 FEBS Journal 277 (2010) 1585–1596 ª 2010 The Authors Journal compilation ª 2010 FEBS
not grossly affected. A more detailed behavioural
examination showed that ADAM10 moderately over-
expressing mice performed similar to controls with
respect to basal activity, exploration and anxiety. In
the Morris water maze hidden platform task, however,
ADAM10 mono-transgenic mice showed thigmotaxis
with floating behaviour, indicating differences in moti-
vation [83]. Therefore, with respect to learning and
memory, mono-transgenic ADAM10 mice displayed
no specific phenotype. By contrast, overexpression of
ADAM10 in an AD mouse model with mutated
human APP created bi-transgenic mice with a clear
improvement of memory and alleviation of learning
deficits [10].
A recent microarray study [119] revealed that there
was only a moderate alteration of gene expression in
moderately ADAM10 overexpressing adult mice.
Genes coding for pro-inflammatory or pro-apoptotic
proteins were not over-represented among differentially
regulated genes and, indeed, a decrease of inflamma-
tion markers was observed. ADAM10 participates also
in the activation of Notch1 signalling by cleaving the

extracellular portion of this receptor upon ligand bind-
ing. Young ADAM10 transgenic mice at postnatal day
15 showed a 40% induction of expression of the gene
for Hes5, whereas a 50% reduction in mice overex-
pressing the dominant negative variant of the enzyme
was reported [119]. Nevertheless, in adult mice, no
significant effects with respect to the amount of
Notch1 target gene Hes5 mRNA were obtained, sug-
gesting an attenuation of the signalling cascade during
ageing. Because ADAM10-based AD therapy will take
place in elderly people, interference with this important
developmental signalling pathway does not appear to
hamper such an approach.
Regarding prion diseases, upregulation of ADAM10
might also be beneficial: the reduction of all species of
the prion protein in ADAM10 overexpressing mice
was accompanied by a prolonged survival time of the
mice after Scrapie infection [63]. In addition, Akt
phosphorylation as a marker for survival signals in
neuronal cells [120] was not affected in ADAM10
moderately overexpressing mice [121]. Furthermore,
the thickness of the myelin sheath was not altered by
ADAM10 overexpression, demonstrating that neuregu-
lin-1 acting as a modulator of this developmental event
is not a substrate of ADAM10 [121]. In mice charac-
terized by high levels of overexpressed ADAM10, how-
ever, phosphorylation of Akt was reduced to  50%
compared to wild-type mice and tomacula-like struc-
tures (i.e. local myelin thickenings) were observed
[121]. In addition, mice with high ADAM10 overex-

pression showed more seizures and stronger neuronal
damage and inflammation than wild-type mice upon
kainate treatment [122]. By contrast, in the presence of
its substrate APP in doses exceeding the endogenous
level, ADAM10 revealed a protective effect [122].
If we consider all of the results obtained concerning
increased ADAM10 activity in vivo, it can be con-
cluded that this approach might be a valuable alterna-
tive to other strategies, such as the inhibition of b-or
c-secretase or immunization, for the treatment of AD.
However, a-secretase activation must be moderate and
closely monitored.
Acknowledgements
The authors’ own work is supported by the Federal
Ministry of Education and Research (BMBF) in the
Framework of the National Genome Research Network
(NGFN), Fo
¨
rderkennzeichen FKZ01GS08130.
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