Amyloid precursor protein gene mutations responsible

Amyloid precursor protein gene mutations responsible

Folia Neuropathol.
Vol. 41, No. 1, pp. 35–40
Copyright © 2003 Via Medica
ISSN 1641–4640
REVIEW ARTICLE
Amyloid precursor protein gene mutations responsible
for early-onset autosomal dominant Alzheimer’s disease
Anna Kowalska
Institute of Human Genetics, Polish Academy of Sciences, Poznań, Poland
According to the “amyloid cascade hypothesis”, the accumulation of Ab peptides in the brain is a primary
event in the pathogenesis of Alzheimer’s disease (AD). Other pathological features (neurofibrillary tangles,
neuronal damage and cell death) are regarded as secondary. One of the strong pieces of evidence supporting this hypothesis was the identification of over 20 pathogenic mutations within the APP gene responsible for familial EOAD. The APP mutations are located close to the sites recognised by the a-, b- and gsecretases. The mutations affect the APP processing, causing overproduction of Ab42 peptide. The imbalance between Ab production and Ab clearance releases a cascade of subsequent cellular processes
leading to AD. In this paper, all APP mutations have been summarised and their molecular effects on the
APP metabolism have been discussed.
key words: Alzheimer’s disease, Ab peptide, amyloid precursor protein, APP gene, mutation,
neurodegeneration
NEUROPATHOLOGICAL HALLMARKS OF AD
Alzheimer’s disease (AD) is characterised by two
major brain lesions, referred to as senile plaques and
neurofibrillary tangles (NFT). Moreover, neuronal cell loss
and synaptic degeneration appear in affected regions
of the brain, first in the hippocampus and entorhinal
cortex, and later in the temporal and parietal lobes,
sometimes also in the frontal and occipital lobes [2].
The senile neuritic plaques are extracellular deposits in
the brain parenchyma, mainly consisting of an amorphous amyloid core, which is stained by b-sheet staining dye Congo red or Thioflavin T. The amyloid-forming
protein, named b-amyloid (Ab), is a peptide of 40–43
residues in length, which is produced by proteolytic cleavages of the longer amyloid precursor protein (APP). The
plaque core is surrounded by dystrophic neurites, acti-
Address for correspondence: Anna Kowalska, PhD
Institute of Human Genetics, Polish Academy of Sciences
ul. Strzeszyńska 32, 60–479 Poznań
tel: (+48 61) 823 30 11 ext. 217, fax: (+48 61) 823 32 35
e-mail: [email protected]
vated microglia and reactive astrocytes, indicating that
amyloid deposition gives rise to inflammatory responses. Ab depositions may also occur as diffuse plaques
(detected only by immunohistochemical methods) and
can also be found in the walls of small cerebral blood
vessels. The neurofibrillary tangles (NFT) are composed
of abnormally phosphorylated tau, a microtubule binding protein. The hyperphosphorylated tau assembles
in paired helical filaments (PHF) and accumulates in
the cytoplasmic compartment of the neurones. In AD
brain, NFT can also appear as ghost cells, having the
shape of death neurones.
APP PROCESSING PATHWAYS
b-amyloid (Ab) is derived by specific endoproteolytic
cleavages of the amyloid precursor protein (APP). The
APP is a type I cell surface glycoprotein. The APP gene
is localised on chromosome 21q21.2 and consists of
18 exons [46]. There are eight isoforms of APP, as
a result of alternative splicing of exons 7, 8 and 15. Exon
7 encodes a Kunitz protease inhibitor (KPI) domain that
inhibits serine proteases such as trypsin, chymotrypsin,
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Folia Neuropathol., 2003, Vol. 41, No. 1
elastase, plasmin and cathepsin D protecting the molecule from degradation [47]. The APP gene is a housekeeping gene since it is expressed abundantly in a variety of tissues. In the brain, APP695 lacking exons 7 and
8 is primarily expressed in neurones [16], while APP lacking exon 15 (the APP751 and APP770 containing KPI
domain) is expressed in microglia, astrocytes and some
neurones. In neurones, the APP is transported from the
cell body to the nerve ending by axonal transport [25].
Our knowledge of APP cellular trafficking remains still
incomplete. After synthesis on ribosomes, APP is translocated into the endoplasmic reticulum and passes
through the secretory pathway to the trans-Golgi network [42]. A small portion of APP molecules reaches
the plasma membrane where it undergoes specific endoproteolysis by three proteases, termed a-, b-, and gsecreatase, respectively. Present candidates for a-secretase activity are three members of the ADAM (a disintegrin and metalloprotease) family: ADAM-9, ADAM-10,
and TACE (tumour necrosis factor-a converting enzyme)/
ADAM-17 [3]. The protein responsible for b-secretase
activity was identified as aspartyl protease and named
BACE (b-site APP-cleaving enzyme) [20, 43]. A large complex of different proteins including presenilins as a part
of a catalytic centre is suggested to be responsible for
a g-secretase cleavage [9]. Due to the action of the secretases, the 40- to 43-residue-long Ab peptide sequence
encoded by a part of exons 16 and 17 is derived from
part of the transmembrane domain, and part of the
extracellular domain of APP molecule (Fig. 1). The
a-secretase cleaves APP inside the b-amyloid sequence
generating not amyloidogenic peptide fragments: a soluble N-terminal part of APP (aAPPs) and a C-terminal
fragment C83 anchored in the membrane. Further
g-secretase cleavage of the C-terminal fragment releases a 3kD peptide p3. The b-secretase cleaves APP at
the N-terminal of the b-amyloid sequence leading to the
formation an N-terminal part of APP (bAPPs) and C-terminal fragment C99. Subsequent cleavage of the C99
protein intermediate at the C-terminal side of the
b-amyloid sequence by the g-secretase generates the
amyloidogenic form of the protein. The g-secretase processing is heterozygenous event forming Ab with different C termini. The Ab40 and Ab42 are the most common forms. The g-secretase usually cuts at Val at position 40 or/and at Ala at position 42 [11]. The specific
functions of both an intact APP protein and peptide fragments formed via proteolytic processing of APP remain
still unclear. APP containing the KPI domain functions
as a protease inhibitor, e.g. it inhibits factor XIa in the
clotting cascade [44]. The soluble APP (APPs) has been
thought to act as an autocrine and neuroprotective fac-
36
Figure 1. A series of endoproteolytic cleavages of the amyloid precursor protein (APP) leading to a formation of non-amyloidogenic (the a-secretase pathway) and amyloidogenic (the
b-secretase pathway) products which are essential for the
pathogenesis of Alzheimer’s disease.
tor [30, 48]. The secreted APPs can also play a role in
the processes of cell-cell and cell-substrate adhesion
[40]. It is likely that this protein is involved in wound
repair and may have a growth-stimulating function.
APP GENE MUTATIONS AND THEIR ROLE IN
b-AMYLOID MISMETABOLISM
In 1991, a missense mutation in APP gene was found
in families suffering from hereditary cerebral haemorrhage with amyloidosis of the Dutch type (HCHWA-D),
a rare autosomal dominant disorder characterised by recurrent cerebral haemorrhages caused by excessive deposition of b-amyloid in the brain blood vessel walls. A missense mutation at codon 693 in exon 17 of the APP gene
(Dutch mutation), causing a Glu to Gln substitution close
to the a-secretase cleavage site of APP is responsible for
HCHWA-D. The discovery of this mutation demonstrated
that APP mutations can lead to b-amyloid deposition. To
date, approximately 20 different AD-related mutations in
exon 16 and 17 of the APP gene have been detected
worldwide (Table 1). All the mutations are located near
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Anna Kowalska, APP mutations in familiar Alzheimer’s disease
Table 1. APP mutations responsible for Alzheimer’s disease and related disorders
Codon/Mutation
AA substitution
Phenotype (age of onset)
References
N665D
Gln Æ Asp
Late-onset AD (86)
[39]
K/M670/671N/L
(Swedish)
Lys-Met Æ
Asn-Leu
FAD (52: 44–59);
increased Ab production
[31]
A673T
Ala Æ Thr
Normal, no disease phenotype
[38]
A692G (Flemish)
Ala Æ Gly
FAD + cerebral hemorrhage (40–60)
increased Ab production
[19]
[7]
E693G
E693G (Arctic)
E693Q (Dutch)
E693K (Italian)
Glu Æ Gly
Glu Æ Gly
Glu Æ Gln
Glu Æ Lys
FAD (58), maybe not pathogenic?
FAD
HCHWA–D, a stroke syndrome
CAA, stroke
[24]
[36]
[28]
[45]
D694N (Iowa)
Asp Æ Asn
CAA
[15]
A713V
A713T
Ala Æ Val
Ala Æ Thr
schizophrenia
FAD (78)
[23]
[4]
T714I (Austrian)
T714A (Iranian)
Thr Æ Ile
Thr Æ Ala
FAD (40)
FAD
[26]
[37]
V715A (German)
V715M (French)
Val Æ Ala
Val Æ Met
FAD (48)
FAD (52: 40–60)
[8]
[1]
I716V (Florida)
I716T
Ile Æ Val
Ile Æ Thr
FAD (55)
[10]
V717F
V717I (London)
Val Æ Phe
Val Æ Ile
FAD (47: 42–52)
FAD (55: 50–60)
increased Ab production
[32]
[13]
[34]
V717G
V717L
Val Æ Gly
Val Æ Leu
FAD (55: 45–62)
EOAD (late 30’s)
[5]
[33]
L723P (Australian)
Leu Æ Pro
FAD
[27]
the critical proteolytic cleavage sites of APP associated
with APP processing and Ab formation (Fig. 2). The age of
onset in patients with APP mutations is usually between
the age of 40–50 and the mean duration of the disease
is 10–15 years. Four different mutations were found at
codon 717 in the APP gene, all causing AD in the fifth
decade of life [5, 13, 32–34]. Carriers of Italian mutation
at codon 693 present with severe cerebral amyloid angiopathy (CAA) and they almost invariably develop stroke
and white matter changes [45]. The Flemish mutation
(A692G) is characterised by CAA, large cored plaques and
NFT. The disease occurs either as progressive dementia,
such as AD, or vascular dementia with stroke-induced
stepwise deterioration [7, 19]. Carriers of Iowa mutation
(D694N) suffer from progressive aphasic dementia. Neuropathological examination revealed Ab plaques and widespread NFT in addition to severe CAA with numerous
cortical haemorrhages and infarctions [15]. A double
mutation was found at codon 670/671 at the N-terminal region of Ab peptide in a large Swedish family with
AD. The Swedish mutation leads to typical symptoms
related to AD [31].
The majority of APP mutations have been found to
affect secretase processing. All of the clearly pathogenic mutations cluster close to b-secretase site after
Met671 ((K/M670/671N/L), a-secretase site after
Lys687 (A692G and E693Q), or g-secretase site after
Thr714 (I716V and V717I). This may suggest that APP
mutations influence the processing of APP. Indeed,
mutations at codons 716 and 717 lead to a selective
increase in the production of Ab peptides ending at residues 42/43. The Swedish mutation at the Ab N terminus increases b-secretase cleavage resulting in an approximate 10-fold increased production of both Ab40
and Ab42/43. APP mutations within codons 692–694
of the APP gene cause amino acid substitutions that
alter biophysical properties of Ab peptide, which affects
the neuropathological distribution of Ab. The Flemish
mutation (A692G) has a more complicated effect on APP
processing, causing impaired a-secretase cleavage, increased heterogeneity of secreted Ab and increased
hydrophobicity of the Ab. Ab with the Flemish mutation
assembles into protofibrils and fibrils at a slower rate
compared to wild type peptide [22]. In contrast, Dutch
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Folia Neuropathol., 2003, Vol. 41, No. 1
Figure 2. A structure of the APP gene. A localisation of the APP mutations cluster within the sequence coding the b-amyloid
peptides (exons 16 and 17 of the APP gene). The arrows (Æ) indicate amino acid substitutions caused by the specific mutations,
while the dropped lines show sites of a-, b-, and g-secretase cleavages.
mutant Ab (E693Q) forms protofibrils and fibrils markedly faster than wild peptide [50]. The Iowa mutation at
codon 694 increases the fibril formation rate of Ab, while
the kinetics and stability of protofibrils are still unknown
[15].
AMYLOID CASCADE HYPOTHESIS
The “amyloid cascade hypothesis” was presented
ten years ago by Selkoe [41] and Hardy [17] to link different pathological findings in AD to a general model.
According to this hypothesis, accumulation of Ab in the
brain is the primary event in the pathogenesis of AD.
Other pathogenic features, such as neurofibrillary tangles, neuronal damage and cell loss, are thought to result from an imbalance between Ab production and Ab
clearance. The “amyloid cascade hypothesis” was based
on several discoveries in AD research. Firstly, the majority of the mutations in the APP and presenilins genes
increase Ab, especially Ab42 production [6]. Secondly,
patients with Down’s syndrome who overexpress APP
due to chromosome 21 trisomy develop Alzheimer-like
symptoms and neuropathology with age [49]. Thirdly,
38
there is a correlation between Ab levels and cognitive
decline in both transgenic animals and Alzheimer’s disease patients [35]. Next, transgenic mice that express
human mutant tau develop NFT but not amyloid plaques
[14]. However, if both mutant human APP and tau is
overexpressed in mice, both tau-positive tangles and
amyloid plaques are formed, the tangle formation is
enhanced compared to the mice expressing tau alone
[29]. In addition, injection of fibrillar Ab42 into mice
expressing human mutant tau increases the numbers
of NFT fivefold. These data suggest that NFT are deposited after changes in Ab metabolism. However, there
are some important critical points of “the amyloid cascade hypothesis”. For example, there is no correlation
between the increase in Ab42 production in patients
with APP or PS mutations and the age of onset of the
disease. In addition, some mutations are associated
with symptoms that are not associated with Alzheimer’s
disease, such as the Flemish and Dutch mutations.
Transgenic mice displaying progressive Ab deposition
do not show clear-cut neuronal loss [12], and transgenic mice expressing familial Alzheimer’s disease muta-
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Anna Kowalska, APP mutations in familiar Alzheimer’s disease
tions fail to develop tau pathology [21]. The following is
the up-to-date sequence of pathogenic events leading
to neurodegeneration in AD proposed by the “amyloid
cascade hypothesis”: 1) both APP and presenilin mutations promote generation of Ab by favoring proteolytic
processing of APP by b- or g-secretase; 2) APP mutations internal to the Ab sequence heighten the self-aggregation of Ab into amyloid fibrils; 3) increased Ab42
production and oligomerisation generate Ab42 deposition as diffuse plaques; 4) Ab oligomers have subtle
effects on the synapses which stimulate microglial and
astrocytic activation, leading to progressive synaptic and
neuritic injury and altered neuronal ionic homeostasis;
5) oxidative injury can alter kinase/phosphatase activities; 6) activation of some kinases (e.g. GSK-3b) precedes hyperphosphorylation of tau and tangles formation; 7) widespread neuronal/neuritic dysfunction results
in cell death with transmitter deficits and subsequently
leads to dementia [18].
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