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| AMYLOID BETA A4 PRECURSOR PROTEIN; APP | |
Alternative titles; symbols
AMYLOID OF AGING AND ALZHEIMER DISEASE; AAA
Masters et al.
(1985) purified and characterized the cerebral amyloid protein that forms
the plaque core in Alzheimer disease (AD; 104300) and
in older persons with Down syndrome. The protein consists of multimeric
aggregates of a polypeptide of about 40 residues (4 kD). The amino acid
composition, molecular mass, and NH2-terminal sequence of this amyloid protein
were found to be almost identical to those described for the amyloid deposited
in the congophilic angiopathy of Alzheimer disease and Down syndrome. Using
computer-enhanced imaging of immunocytochemical stains of Alzheimer disease
prefrontal cortex, Majocha et al. (1988)
described the distribution of amyloid protein deposits exclusive of other senile
plaque components.
APP has several isoforms generated by alternative splicing of a 19-exon gene:
exons 1-13, 13a, and 14-18 (Yoshikai et al., 1990). The
predominant transcripts are APP695 (exons 1-6, 9-18, not 13a), APP751 (exons
1-7, 9-18, not 13a), and APP770 (exons 1-18, not 13a). All of these encode
multidomain proteins with a single membrane-spanning region. They differ in that
APP751 and APP770 contain exon 7, which encodes a serine protease inhibitor
domain. APP695 is a predominant form in neuronal tissue, whereas APP751 is the
predominant variant elsewhere. Beta-amyloid is derived from that part of the
protein encoded by parts of exons 16 and 17.
By in situ hybridization, Robakis et al. (1987) showed
that the beta-amyloid probe maps to the proximal part of 21q21. (See 104300 for
a discussion of the mapping of Alzheimer disease to approximately the same
region of chromosome 21, 21q11.2-q21.) Additional, but weaker hybridization was
observed on chromosome 20 within band 20p12, a region in which the gene for
prion protein (176640) is
located. Tanzi et
al. (1987) mapped the amyloid beta protein gene to 21q11.2-q21 by analysis
of somatic cell hybrid cDNAs. They also observed putative crossovers between the
CVAP gene and familial Alzheimer disease. Zabel et al. (1987) mapped
the A4 precursor gene within band 21q21 by in situ hybridization. They placed it
near or in the 21q21-q22.1 segment, a somewhat more distal location than that
suggested by Robakis et al. (1987). By
studies of DNA from a panel of somatic cell hybrids, Lovett et al. (1987)
demonstrated that the homologous gene in the mouse is on chromosome 16, and Cheng et al.
(1987) mapped the amyloid beta protein gene to mouse chromosome 16 by
genetic linkage studies. Using a cDNA probe for the gene encoding the
beta-amyloid protein of Alzheimer disease, Delabar et al. (1987) found
that leukocyte DNA from 3 patients with sporadic Alzheimer disease and 2
patients with karyotypically normal Down syndrome contained 3 copies of this
gene. Because a small region of chromosome 21 containing the ETS2 gene (164740) was
duplicated in patients with Alzheimer disease as well as in karyotypically
normal Down syndrome, they suggested that duplication of a subsection of the
critical segment of chromosome 21 that is duplicated in Down syndrome might be
the genetic defect in Alzheimer disease. On the other hand, Tanzi et al. (1987) found
that the amyloid gene was not duplicated in sporadic Alzheimer disease.
Van
Broeckhoven et al. (1987) studied 2 large pedigrees in which Alzheimer
disease was inherited in a clearly autosomal dominant manner. One pedigree
contained 36 patients in 6 generations; in 10, the diagnosis had been
histologically confirmed. The second pedigree showed 22 patients in 5
generations with 5 histopathologically confirmed cases. In 5 families the
disease manifested a juvenile form; mean age of onset was 33.1 years in 1 family
and 34.4 years in the other. Four nuclear families with senile onset after age
65 were incorporated in the linkage calculation. All lod scores for linkage of
A4 amyloid cDNA clone and Alzheimer disease were negative. In 2 of the families
a recombinant was found, proving that the amyloid protein is not the site of the
mutation causing Alzheimer disease. In 1 of the patients in whom Delabar et al. (1987)
demonstrated an apparent duplication of the CVAP gene, an 86-year-old female
Alzheimer patient, and in a normal 86-year-old female control, Blanquet et al. (1987) studied
in situ hybridization using a cDNA probe. These results allowed assignment of
the locus to the mid-part of 21q near the interface of q21 and q22, i.e.,
subbands q21.3 and q22.11. There was absence of hybridization elsewhere in the
genome. The grain counts in the patient and the control were compatible with
gene dosage due to duplication of the gene in Alzheimer disease. In an attempt
to define more precisely the region of chromosome 21q containing the beta
amyloid gene, Jenkins et al. (1988) used in
situ hybridization and Southern blot techniques on skin fibroblast lines
carrying translocations involving chromosome 21. Their findings concur with the
previous report of Robakis et al. (1987) and
indicate that the gene is within the region 21q11.2-q21.05. By means of somatic
cell hybrid mapping panel, in situ hybridization, and
transverse-alternating-field electrophoresis, Patterson et al. (1988)
showed that the APP gene is located very near the 21q21/21q22 border and
probably within the region of chromosome 21 that, when trisomic, results in Down
syndrome. On the other hand, Korenberg et al. (1989)
concluded that the APP gene is located outside the minimal region producing the
classic phenotypic features of Down syndrome.
Tanzi et al.
(1992) reported on the findings of a multicenter, multifaceted study to
evaluate the possible role of APP mutations in familial and sporadic Alzheimer
disease. Their final conclusion was that APP gene mutations account for a very
small portion of familial Alzheimer disease. Although mutations of APP have been
detected in a few FAD families (see 104760.0002,
104760.0003,
and 104760.0004),
obligate crossovers between APP and FAD have been reported in several pedigrees
including FAD4, a large kindred in which Tanzi et al. (1987) found
highly suggestive evidence for linkage of the disorder to chromosome 21. No
mutations were found in the APP gene when the entire coding region was sequenced
in family FAD4 and also in FAD1, a second large kindred. Thus in at least one
chromosome 21-linked FAD pedigree, the gene defect is not accounted for by a
mutation in the known coding region of the APP gene. Furthermore, none of 25
well characterized early- and late-onset FAD pedigrees yielded positive lod
scores at a recombination fraction of 0.0 for linkage to the APP gene. Tanzi et al.
(1992) also sequenced exons 16 and 17 (which code for the beta-A4 domain of
APP) in 30 (20 early- and 10 late-onset) FAD kindreds and in 11 sporadic AD
cases, and screened 56 FAD kindreds and 81 cases of sporadic AD for the presence
of the originally reported FAD-associated mutation val717-to-ile, using BclI
digestion. No APP gene mutation was found in any of the families or sporadic
cases examined. A collaborative study similar to that of Tanzi et al. (1992) was
reported by Kamino et al. (1992), who
used linkage and mutational analysis to arrive at the same conclusion, namely,
that APP mutations account for AD in only a small fraction of FAD kindreds.
Three separate mutations in codon 717 of the APP transcript have been found
in familial Alzheimer disease: val717-to-ile (104760.0002),
val717-to-phe (104760.0003),
and val717-to-gly (104760.0004).
The location of these mutations and that of the double mutation discussed in 104760.0008
suggested to Suzuki et al. (1994) that
they may cause Alzheimer disease by altering beta-APP processing in a way that
is amyloidogenic. They found that the APP717 mutations were consistently
associated with a 1.5- to 1.9-fold increase in the percentage of longer
fragments generated and that the longer fragments formed insoluble amyloid
fibrils more rapidly than did the shorter ones.
The major protein subunit (A4) of the amyloid fibril of tangles, plaques, and
blood vessel deposits is a polypeptide identified as the cleavage product of a
larger precursor protein with features of a cell surface receptor (Kang et al.,
1987). Van
Nostrand et al. (1989) presented evidence that protease nexin-II, a protease
inhibitor that is synthesized and secreted by various cultured extravascular
cells, is identical to APP. Smith et al. (1990) showed
that the platelet inhibitor of coagulation factor XI (264900) is
a secreted form of Alzheimer amyloid precursor protein. Schmaier et al. (1993)
provided biochemical evidence that PN-2 may serve as a cerebral anticoagulant.
Schmaier et al.
(1993) found that PN-2 is also a potent inhibitor of factor IXa (306900) and
that it forms a complex with factor IXa as detected by gel filtration and ELISA.
They suggested that this fact may explain the spontaneous intracerebral
hemorrhages seen in patients with hereditary cerebral hemorrhage with
amyloidosis of the Dutch type in which there is extensive accumulation of
PN-2/APP-beta in cerebral blood vessels (104760.0001).
Adler et al.
(1991) used the process of cellular senescence as a model to study the role
of beta-amyloid precursor protein in biologic aging. They demonstrated a
dramatic increase in amyloid mRNA production and a more modest increase in the
protein synthesized in senescent cultured fibroblasts compared with
early-passage proliferating fibroblasts. They found, moreover, that induction of
quiescence by serum deprivation may reversibly induce an increase in amyloid
mRNA and protein levels. The investigators hypothesized that the beta-amyloid
precursor protein may play an important role in the cellular growth and
metabolic responses to serum and growth factors under both physiologic and
pathologic conditions. Bakker et al. (1991) described
the use of a mutation-specific oligonucleotide in the diagnosis of this
disorder. The normal cellular function of APP is unknown.
Multhaup et al. (1996) demonstrated that the amyloid precursor protein is involved in copper reduction. They postulated that copper-mediated toxicity may contribute to neurodegeneration in Alzheimer disease, possibly by increased production of hydroxyl radicals.
Yan et al.
(1996) reported that the AGER protein (600214),
called RAGE (receptor for advanced glycation end products) by them, is an
important receptor for the amyloid beta peptide and that expression of this
receptor increases in Alzheimer disease. They noted that expression of RAGE is
particularly increased in neurons close to deposits of amyloid beta peptide and
to neurofibrillary tangles.
Kaneko et al. (1995) demonstrated that nanomolar concentrations of various synthetic beta amyloids specifically impaired mitochondrial succinate dehydrogenase, and speculated that one of the primary targets of beta amyloids is the mitochondrial electron transport chain.
Alternative splicing of transcripts from the single APP gene results in at
least 10 isoforms of the gene product (Sandbrink et al., 1994), of
which APP695 is preferentially expressed in neuronal tissues. In 3 mutations,
valine-642 in the transmembrane domain of APP695 is replaced by isoleucine (104760.0002),
phenylalanine (104760.0003),
or glycine (104760.0004)
in association with dominantly inherited familial Alzheimer disease. (According
to an earlier numbering system, val642 was numbered 717 and the 3 mutations were
V717I, V717F, and V717G, respectively.) Yamatsuji et al. (1996)
stated that these 3 mutations account for most, if not all, of the chromosome
21-linked Alzheimer disease. In transgenic mice, overexpression of such mutants
mimics the neuropathology of AD. Yamatsuji et al. (1996)
demonstrated that expression of any 1 of these 3 mutant proteins, but not of
normal APP695, induced nucleosomal DNA fragmentation in cultured neuronal cells.
Induction of DNA fragmentation required the cytoplasmic domain of the mutants
and appeared to be mediated by heterotrimeric guanosine triphosphate-binding
proteins (G proteins).
Di Luca et al.
(1998) found that the ratio of the 130-kD isoform to that of lower molecular
weight 106- to 110-kD isoforms of APP was significantly altered in platelet
membranes derived from Alzheimer patients compared with that in controls. No
differences were observed in the relative levels of mRNA corresponding to the 3
major transcripts, APP770, APP751 and APP695. The authors suggested that
Alzheimer disease is a systemic disorder, with oversecretion of APP751 and
APP770 as well as an alteration of processing of mature APP in platelets and
neurons.
The protein deposits in neurofibrillary tangles, neuritic plaques, and
neuropil threads in the cerebral cortex of patients with Alzheimer disease and
Down syndrome (190685)
contain forms of beta-amyloid precursor protein and ubiquitin-B (191339)
that are aberrant in the C terminus. These proteins are not found in young
control subjects, whereas the presence of anomalous UBB in elderly control
patients may indicate early stages of neurodegeneration. The 2 species of
aberrant proteins were found by van Leeuwen et al. (1998) to
display cellular colocalization, suggesting a common origin, operating at the
transcriptional level or by posttranscriptional editing of RNA. This type of
transcript mutation is likely an important factor in the widely occurring
nonfamilial early- and late-onset forms of AD. The aberrant proteins were not
found in patients with Parkinson disease (168600).
Using 2 different sensitive approaches, van Leeuwen et al. (1998)
failed to find any indication of the mutation at the genomic level. The finding
that frameshift mutations occur in multiple proteins within the same neuron
suggested that a common denominator in the transcription-propagating events was
involved. The mechanism of transcript mutation, which was a dinucleotide
deletion (delta-GA, delta-GT, or delta-CT), was unclear. The frequently mutated
motif in exon 9 of the APP gene, GAGAGAGA, is an extended version of the GAGAG
in the vasopressin gene (192340),
which shows a GA deletion in vasopressin transcripts of the homozygous
Brattleboro rats with diabetes insipidus. The authors commented that transcript
mutations may be a widely occurring phenomenon. In principle, each transcript
containing a susceptible motif, such as GAGAG, could undergo such a process. Van Leeuwen et al.
(1998) stated that the process is probably not limited to postmitotic cells;
however, postmitotic neurons are less capable of compensating for
transcript-modifying activity and are thus particularly sensitive to the
accumulation of frameshifted proteins. Thus, during aging, single neurons may
generate and accumulate abnormal proteins, consequently leading to cellular
disturbances and causing degeneration. The mechanism of dinucleotide deletion at
the transcript level may well underlie a number of neurodegenerative
pathologies. Destabilizing genomic dinucleotide motifs predisposing to mRNA
transcript mutations had previously been described in vasopressin-deficient
rats.
Gervais et al.
(1999) found that APP is directly and efficiently cleaved by caspases during
apoptosis, resulting in elevated amyloid-beta peptide formation. The predominant
site of caspase-mediated proteolysis is within the cytoplasmic tail of APP, and
cleavage at this site occurs in hippocampal neurons in vivo following acute
excitotoxic or ischemic brain injury. Caspase-3 (600636) is
the predominant caspase involved in APP cleavage, consistent with its marked
elevation in dying neurons of Alzheimer disease brains and colocalization of its
APP cleavage product with amyloid-beta in senile plaques. Caspases thus appear
to play a dual role in proteolytic processing of APP and the resulting
propensity for amyloid-beta peptide formation, as well as in the ultimate
apoptotic death of neurons in Alzheimer disease.
Tang et al.
(1996) presented evidence suggesting that postmenopausal estrogen
replacement therapy may prevent or delay the onset of AD. Xu et al. (1998) presented
evidence that physiologic levels of 17-beta-estradiol reduce the generation of
beta-amyloid by neuroblastoma cells and by primary cultures of rat, mouse, and
human embryonic cerebrocortical neurons. These results suggested a mechanism by
which estrogen replacement therapy can delay or prevent AD.
To the time of the report by De Jonghe et al. (1998), 5
missense mutations had been identified in APP that result in early-onset AD: the
Swedish APP670/671 double mutation (104760.0008);
3 different mutations at codon 717: the London APP717 mutation, V717I (104760.0002),
V717F (104760.0003),
and V717G (104760.0004);
and the Florida APP716 mutation (104760.0006).
All of these AD-related mutations involved codons near the beta- and
gamma-secretase cleavage sites in APP. Two other missense mutations in the APP
gene are located within A-beta near the alpha-secretase cleavage site: the
Flemish APP692 mutation (104760.0005),
which is associated with cerebral hemorrhage due to congophilic amyloid
angiopathy or with early-onset AD with onset age in the mid-forties; and the
Dutch APP693 mutation (104760.0001).
While a common effect of AD-linked mutations is to elevate extracellular
concentrations of A-beta-42, not much had been known about the effect of APP692
and APP693. De
Jonghe et al. (1998) provided evidence that APP692 and APP693 have a
different effect on A-beta secretion as determined by cDNA transfection
experiments. While APP692 upregulates both A-beta-40 and A-beta-42 secretion,
APP693 does not. These data corroborate the previous findings that increased
A-beta secretion, and particularly increased secretion of A-beta-42, is specific
for AD pathology.
Lorenzo et al.
(2000) demonstrated that conversion of amyloid beta to the fibrillar form
markedly increased binding to specific neuronal membrane proteins, including
APP. Nanomolar concentration of fibrillar amyloid beta bound cell surface
holo-APP in cortical neurons. Reduced vulnerability of cultured APP-null neurons
to amyloid beta neurotoxicity suggested that amyloid beta neurotoxicity involves
APP. When fibrillar amyloid beta protein was incubated with cortical cells from
mice that lacked the APP gene, a reduction in toxicity of 20 to 30% was
observed, suggesting that while APP may be one of the major cell surface
mediators of amyloid beta toxicity, a large part of the toxic effect must be due
to other mechanisms (Senior, 2000).
As pointed out by Miravalle et al. (2000), 3
different mutations have been described in codon 693 resulting in an amino acid
substitution at position 22 of A-beta: glu22 to gln (104760.0001),
the 'Dutch mutation'; glu22 to gly (104760.0013),
the 'Arctic mutation'; and glu22 to lys (E22K; 104760.0014),
the 'Italian mutation.' In addition, a C-to-G transversion in codon 692 resulted
in an ala21-to-gly amino acid substitution (104760.0005),
the 'Flemish mutation.' Patients carrying the E22Q variant usually present with
lobar cerebral hemorrhages before 50 years of age. The E22K mutation, on the
other hand, was described in several members of 3 Italian kindreds who presented
with recurrent hemorrhagic strokes associated with extensive cerebrovascular
amyloid deposition late in life, between 60 and 70 years of age. Miravalle et al. (2000)
compared the Dutch and Italian variants and the wildtype peptide. They also
evaluated the cytotoxic effects of the peptides on human cerebral endothelial
cells in culture. Under the conditions tested, the E22Q peptide exhibited the
highest content of beta-sheet conformation and the fastest
aggregation/fibrillization properties. The Dutch variant also induced apoptosis
of cerebral endothelial cells at a concentration of 25 microM, whereas the
wildtype A-beta and the E22K mutant had no effect. The data suggested that
different amino acids at position 22 confer distinct structural properties to
the peptides that appear to influence the onset and aggressiveness of the
disease rather than the phenotype.
Calhoun et al.
(1998) studied the pattern of neuron loss in transgenic mice expressing
mutant human APP with the 'Swedish mutation' (104760.0008).
These mice develop APP-immunoreactive plaques, primarily in neocortex and
hippocampus, progressively with age (Sturchler-Pierrat et al.,
1997). Calhoun
et al. (1998) showed that formation of amyloid plaques can lead to
region-specific loss of neurons in the transgenic mouse. Neuron loss was
observed primarily in the vicinity of plaques, but intraneuronal amyloidogenic
APP processing could not be excluded as an additional cause. The extent of the
observed loss was less than that reported in end-stage AD, possibly because
overexpression of APP in the transgenic mouse has a neuroprotective effect. It
is also likely that neuron loss would increase in these mice with further aging.
Games et al.
(1995) created a mouse model for Alzheimer disease by producing transgenic
mice overexpressing the V717F beta-amyloid precursor protein. The brains showed
typical pathologic findings of AD, including numerous extracellular thioflavin
S-positive A-beta deposits, neuritic plaques, synaptic loss, astrocytosis, and
microgliosis.
Using the PDAPP transgenic mouse (which overexpresses V717F mutant APP
protein), Schenk
et al. (1999) studied the effect of immunization with amyloid beta-42 on
disease progression. Transgenic animals were immunized either before the onset
of Alzheimer disease-type neuropathology (at 6 weeks of age) or at an older age
(11 months) when amyloid-beta deposition and several of the subsequent
neuropathologic changes were well established. Schenk et al. (1999) reported
that immunization of the young animals essentially prevented the development of
beta-amyloid plaque formation, neuritic dystrophy, and astrogliosis. Treatment
of the older animals also markedly reduced the extent and progression of these
AD-like neuropathologies. Animals who began treatment at 11 months of age showed
greater than 99% reduction of amyloid beta-42 burden at 18 months of age
compared with untreated littermates. Schenk et al. (1999) stated
that the almost complete absence of plaques in the brains of amyloid
beta-42-treated mice indicated that a fundamental mechanism of amyloid plaque
formation had been disrupted. Subsequent studies showed that the amyloid-beta
production itself was unaffected. Therefore, amyloid beta-42 immunization either
prevents deposition and/or enhances the clearance of amyloid-beta from the
brain. The absence of neuritic and gliotic changes indicated that amyloid
beta-42 immunized mice never developed the neurodegenerative lesions that typify
the progression of AD-like pathology in this model. The absence of enhanced
astrocytosis, in particular, suggested that the processes preventing
beta-amyloidosis do not in themselves cause appreciable damage to the neuropil.
Schenk et al.
(1999) suggested that amyloid-beta immunization may prove beneficial for
both the treatment and prevention of Alzheimer disease.
Hsiao et al.
(1996) produced transgenic mice overexpressing the 695-amino acid isoform of
human APP containing a K670N, M671L double mutation which was described by Mullan et al.
(1992) in a large Swedish family with early-onset Alzheimer disease.
Transgenic mice overexpressing this protein had normal learning and memory in
spatial reference and alternation tasks at 3 months of age but showed impairment
by 9 to 10 months of age. Hsiao et al. (1996) reported
that a 5-fold increase in the concentration of the beta amyloid derivatives was
found in the brains of the older transgenic mice. Classic senile plaques with
dense amyloid cores were present in mice with elevated brain beta amyloid. The
results reported by Hsiao et al. (1996)
demonstrated the feasibility of creating transgenic mice with robust behavioral
and pathologic features of Alzheimer disease.
Citron et al.
(1997) noted that several lines of evidence strongly support the conclusion
that progressive cerebral deposition of amyloid beta protein is a seminal event
in familial Alzheimer disease (FAD) pathogenesis. They carried out experiments
to test the hypothesis that FAD mutations act by fostering deposition of amyloid
beta protein particularly in the highly amyloidogenic 42-residue form described
by Jarrett et al.
(1993). Citron et al. (1997)
established transfected cell lines and transgenic mouse models that coexpress
human presenilins PS1 (104311) or
PS2 (600759) and
human amyloid beta precursor and analyzed quantitatively the effects of
presenilin expression on APP processing. They demonstrated that in both model
systems, expression of wildtype presenilin genes did not alter APP levels,
alpha- and beta-secretase activity, and beta amyloid production. PS1 and PS2
mutations in the transfected cells caused a highly significant increase in
secretion of amyloid beta-42 in all mutant clones. Their data raised the
possibility of an intrinsic difference in the effects of PS1 and PS2 mutations
on APP processing. The PS2 Volga mutation (600759.0001)
led to a 6- to 8-fold increase in the production of total amyloid beta-42; none
of the PS1 mutations had such a dramatic effect. Citron et al. (1997) noted
that transgenic mice carrying mutant PS1 genes differed from transgenic mice
carrying wildtype PS1 genes in that the mutation-carrying transgenic mice
overproduced amyloid beta-42 in the brain, which was detectable at 2 to 4 months
of age. Citron et
al. (1997) stated that their combined in vitro and in vivo data clearly
demonstrated that the FAD-linked presenilin mutations directly or indirectly
altered the level of gamma-secretase (but not of alpha- or beta-secretase). This
increase in gamma-secretase resulted in increased proteolysis of APP at the
amyloid beta-42 site, leading to heightened amyloid beta-42 production. They
noted that elucidating the biologic mechanism of this effect could lead to
therapeutic inhibition of amyloid beta-42 production in order to prevent or slow
the progress of Alzheimer disease.
Meziane et al.
(1998) reported memory-enhancing effects of secreted forms of the
beta-amyloid precursor protein in normal and amnestic (forgetful) mice. When
administered intracerebroventricularly into mice performing various learning
tasks involving either short-term or long-term memory, the APP751 and APP695
secreted forms of APP had potent memory-enhancing effects and blocked learning
deficits induced by scopolamine. The memory-enhancing effects of APP(s) were
observed over a wide range of very low doses, blocked by anti-APP(s) antisera,
and observed when APP(s) was administered either after the first training
session in a visual discrimination or a lever-press learning task or before the
acquisition trial in an object recognition task. APP(s) had no effect on motor
performance or exploratory activity. The APP695 and APP751 forms were equally
effective in the object recognition task, suggesting that the memory-enhancing
effect does not require the Kunitz protease inhibitor domain. Sisodia and Gallagher (1998)
reviewed what had been learned about APP function but forewarned that there was
no consensus. Several lines of evidence suggested that APP may play a role in
synapse formation and maintenance. The findings in knockout mice were reviewed.
They commented that the studies by Meziane et al. (1998) suggest
that secretory APP alters the function of cholinergic neurons or their targets
because impairment caused by administration of scopolamine was alleviated by
concurrent peptide treatment.
Bales et al.
(1999) quantified the amount of amyloid beta-peptide immunoreactivity as
well as amyloid deposits in a large cohort of transgenic mice overexpressing the
V717F human amyloid precursor protein, with no, 1, or 2 mouse apolipoprotein E
alleles at various ages. Remarkably, no amyloid deposits were found in any brain
region of V717F heterozygous mice that were ApoE -/- as old as 22 months of age,
whereas age-matched V717F heterozygous animals which were either ApoE +/- or
ApoE +/+ displayed abundant amyloid deposition. The amount of A-beta
immunoreactivity in the hippocampus was also markedly reduced in an ApoE gene
dose-dependent manner, and no A-beta immunoreactivity was detected in the
cerebral cortex of V717F heterozygous mice that were ApoE -/- at any of the time
points examined. Because the absence of ApoE altered neither the transcription
nor the translation of the APP(V717F) transgene nor its processing to A-beta
peptide(s), Bales
et al. (1999) postulated that ApoE promotes both the deposition and
fibrillization of A-beta, ultimately affecting clearance of protease-resistant
A-beta/ApoE aggregates. ApoE appears to play an essential role in amyloid
deposition in brain, one of the neuropathologic hallmarks of Alzheimer disease.
In 2 generations and 5 sibships of a Dutch family reported by Wattendorff et al. (1982), 11
persons suffered cerebral and cerebellar hemorrhage and infarction at ages
ranging from 44 to 58 years. The principal clinical characteristic was recurring
cerebral hemorrhages, sometimes preceded by migrainous headaches or mental
changes. In 6 autopsied cases and 1 biopsy specimen, hyaline thickening of the
walls of cortical arterioles was found. The arteries of the arachnoid showed
marked tortuosity, concentric proliferation, and focal hyalinization. Amyloid
was demonstrated in the hyalinized vessels but was not found outside the nervous
system. The kindred of Wattendorff et al. (1982) was
from Scheveningen. Luyendijk and Bots (1986)
wrote: 'As the hereditary disease is well-known to the co-members of the
respective families they usually inform the doctors on the probable diagnosis
themselves, when such a patient is admitted into the hospital. Besides which
they usually add all kinds of genealogical information.' In studies of the Dutch
form of hereditary cerebral hemorrhage with amyloidosis, van Duinen et al. (1987)
demonstrated that the vascular amyloid deposits are related to the beta-protein
associated with Alzheimer disease and Down syndrome; thus there are at least 2
forms of hereditary cerebral hemorrhage with amyloidosis: the Icelandic type (105150),
due to a defect in cystatin C (CST3; 604312),
and the Dutch type, due to a defect in CVAP. Luyendijk et al. (1988)
described 136 patients with hereditary cerebral hemorrhage, all belonging to
families originally resident in Katwijk, The Netherlands. No genealogic
connection has been established between the Dutch and Icelandic pedigrees The
findings in all of the Dutch cases are identical and differ from the findings in
the Icelandic cases. Icelandic patients suffer the first stroke at the mean age
of 27 years, whereas the Dutch patients are approximately 25 years older; the
level of cystatin C in the cerebrospinal fluid of Icelandic patients is
decreased as compared to Dutch patients and healthy persons; and
immunohistochemically, intense staining for cystatin C is found in diseased
Icelandic blood vessels, whereas in the Dutch material only weak or dubious
staining is found. Luyendijk et al. (1988) had
78 males and 58 females in their series; the sex ratio for the proven cases was
nearly equal (29 males and 26 females). There were numerous examples of
father-to-son transmission. By linkage analysis (Van Broeckhoven et al., 1990)
and by demonstration of a specific intragenic lesion (Levy et al., 1990), the
amyloid beta-protein precursor gene has been shown to be the site of the
mutation in the Dutch form of cerebroarterial amyloidosis. The amyloid precursor
proteins in the Dutch and Icelandic forms of cerebroarterial amyloidosis are
both protease inhibitors and both have been found to have a substitution in
their genes that give rise to a substitution of glutamine. In 2 patients from
presumably unrelated Dutch families, Levy et al. (1990)
demonstrated a guanine-to-cytosine change at nucleotide 1852 resulting in a
substitution of glutamine for glutamic acid at position 22 of the amyloid
protein (codon 693 of APP). Prelli et al. (1990)
demonstrated that both the normal and the variant alleles are expressed in
vascular amyloid in this disorder. Haan et al. (1990) found that
all 16 patients they examined with the Dutch type of hereditary cerebral
hemorrhage with amyloidosis had psychiatric abnormalities; dementia was present
in 12. Three patients tested twice at an interval of some years exhibited
progressive intellectual deterioration and memory disturbance; in 2 of them
there was no evidence of intercurrent strokes. Fernandez-Madrid et al.
(1991) identified the mutation in a woman of Dutch extraction living in the
United States. The patient was a normotensive 63-year-old woman who was well
until age 47 when she began to have attacks approximately every 2 weeks. Graffagnino et al.
(1994) failed to find the amyloid mutation in any of 48 consecutive patients
with intracerebral hemorrhage admitted to Duke University Hospital. No
pathologic examinations were made to determine if any of these patients had
amyloid deposition.
In 2 families with Alzheimer disease, Goate et al. (1991) found a
C-to-T transition at base 2149 in exon 17 of the APP gene causing a
valine-to-isoleucine change at amino acid 717. This valine residue is conserved
in rodents. The mutation may have involved a CpG dinucleotide. The substitution
created a BclI restriction site which allowed detection of the corresponding
change within the PCR product. This finding required reexamination of previous
work mapping Alzheimer disease to chromosome 21. In some families the AD gene
appeared to be close to the APP gene, but the genes were thought to be distinct
because of recombinants in some families. In general, however, late-onset
families did not show linkage to chromosome 21 markers, and even some families
with early-onset disease did not show that linkage. Other mutations in the APP
gene may be identified as the basis of Alzheimer disease. The occurrence of
pathologic changes of Alzheimer disease in trisomy 21 suggests that these
mutations need not be in the coding region but may also be in controlling
elements, leading to overexpression of APP. In the first family studied by Goate et al.
(1991), the average age of onset was 57 +/- 5 years. It is noteworthy that
exon 17 is the site of the mutation in the Dutch type of cerebral arterial
amyloidosis. The same mutation was found by Naruse et al. (1991) in 2
separate Japanese cases of familial early-onset Alzheimer disease, and Yoshioka et al.
(1991) found it in a third Japanese family in the course of studying 6 FAD
families and 3 sporadic early-onset AD patients. On the other hand, van Duijn et al.
(1991) failed to find the mutation in any of 100 early-onset patients. They
concluded that at a confidence level of 95% this finding suggested that the
val717-to-ile mutation accounts for less than 3.6% of all cases with early-onset
AD. Schellenberg
et al. (1991) sought the val717-to-ile mutation in 76 families with familial
Alzheimer disease, in 127 subjects with presumably sporadic Alzheimer disease,
in 16 Down syndrome cases, and in 256 normal controls; none was positive. In the
same cases they also found no example of the mutation associated with the Dutch
type of cerebroarterial amyloidosis (104760.0001).
Karlinsky et
al. (1992) stated that 8 pedigrees with the val717-to-ile mutation had been
reported and that this mutation accounts for only about 3% of familial Alzheimer
disease and for none of sporadic Alzheimer disease. They studied in detail a
family from Toronto in which the Koch postulates were satisfied: 1) presence and
cosegregation of the mutation with the disease in affected members; 2) absence
of the mutation from unaffected members; and 3) re-creation of the phenotype in
transgenic or transfection models. (The third postulate was not addressed in
their report.) The disorder in this family was presenile in onset, with earliest
manifestations related to deficits in memory, cognitive processing speed, and
attention to complex cognitive sets. The family immigrated to Canada from the
British Isles in the 18th century. Relationship to one or both of the pedigrees
with the val717-to-ile mutation reported by Goate et al. (1991) could not
be excluded. St.
George-Hyslop et al. (1994) pointed out that the family contained one member
who had the val717-to-ile mutation but remained clinically healthy with no sign
of disease on neurologic or neuropsychologic tests or on computerized axial
tomography or magnetic resonance imaging scans at an age 2 standard deviations
beyond the mean age of onset in this pedigree. They suggested that this might be
due to the fact that this individual lacked the E4 allele at the APOE locus (107741),
his genotype being E2/E3. All 3 living clinically affected family members with
the val717-to-ile mutation were considerably younger and had the E3/E4 genotype.
St. George-Hyslop
et al. (1994) suggested that there is an interaction between the development
of Alzheimer disease due to mutations in the APP gene and the E4 allele. In
contrast, they observed no relationship between the APOE genotype and age of
onset or other clinical features in affected members of a large pedigree in
which familial AD was linked to chromosome 14 (104311).
Maruyama et
al. (1996) explored the significance of the fact that 3 mutations in the
val717 residue of APP (to ile, phe, or gly) have been found in familial
Alzheimer disease and that these mutations increase secretion of A-beta-42(43).
To study the specificity of the effects of these mutations on APP processing,
they transiently expressed APP genes with mutations of val717 to lys, ser, glu,
or cys in COS cells. The 3 mutations associated with FAD increased the levels or
ratios of A-beta-42(43), whereas the secretion of A-beta-40 was decreased. Other
mutations irrelevant to FAD, except val717 to lys, had little effect on the
ratio of beta-42(43). Substitution to lys decreased the secretion of beta-42.
Overall, the results suggested a specific role of the val717 residue in APP
processing and, especially, in gamma-cleavage.
In DNA from affected members of a family with autopsy-proven Alzheimer
disease, Murrell
et al. (1991) found substitution of phenylalanine for valine at position
717. This position is the same as that of the valine-to-isoleucine substitution
found by Goate et
al. (1991) in another family with early-onset hereditary Alzheimer disease.
It is 2 residues beyond the carboxyl terminus of the beta-amyloid peptide
subunit isolated from amyloid fibrils. The mutation specifically involved change
of GTC (val) to TTC (phe). Zeldenrust et al. (1993)
found 9 examples of the phe717 mutation among 34 at-risk members of the original
Indiana FAD kindred. Zeldenrust et al. (1993)
tested for the 3 known mutations at codon 717 of APP in 145 FAD subjects and
found none positive for a mutation in that position. Farlow et al. (1994) reviewed
the clinical characteristics of the disorder in the family reported by Murrell et al.
(1991). Recent memory, information-processing speed, sequential tracking,
and conceptual reasoning were the earliest cognitive functions affected.
Language and visuoperceptual skills were largely spared early in the course of
the disease. Later there were progressive cognitive deficits and inability to
perform the activities of daily living. Death occurred, on average, 6 years
after onset. The family was Romanian, many of its members having migrated to
Indiana. The mean age of onset of dementia was 43 years.
Chartier-Harlin et al. (1991)
demonstrated a third mutation in codon 717 in a family with Alzheimer disease
with onset at an average age of 59 +/- 4 years. Linkage analysis had shown a
peak lod score of 3.02 at theta = 0.0 between the disease and marker D21S210
which is located close to the APP gene. Sequencing of exon 17 showed a T-to-G
transversion at basepair 2150, changing valine to glycine at codon 717 of the
APP transcript.
In a 4-generation Dutch family, Hendriks et al. (1992)
identified an ACG-to-AGG mutation at codon 692 which cosegregated with presenile
dementia and cerebral hemorrhage due to cerebral amyloid angiopathy. The
ala692-to-gly mutation was in the same exon of the APP gene as the 3 mutations
in codon 717.
Cras et al.
(1998) described the postmortem examination of 2 demented patients with the
A692G mutation. The autopsy findings supported the diagnosis of Alzheimer
disease in both patients. Furthermore, the neuropathologic abnormalities were
remarkable for the large amyloid core senile plaques, the presence of
neurofibrillary tangles, and extensive amyloid angiopathy. Leptomeningeal and
parenchymal vessels showed extensive deposition of A-beta amyloid protein. The
morphology of the senile plaques was clearly distinct from that described in
sporadic and chromosome 14-linked AD patients, in patients with the APP717-ile
mutation (104760.0002)
causing familial presenile AD, and in patients with the APP693-gln mutation (104760.0001)
causing the Dutch form of cerebroarterial amyloidosis.
Among 105 patients with definite or probable Alzheimer disease or atypical
dementia and chronic schizophrenia, Jones et al. (1992)
identified a single abnormality of APP in a chronic schizophrenic with cognitive
defects. A C-to-T transition resulted in substitution of valine for alanine-713.
The mutation was not detected in other members of the patient's family (other
affected individuals were deceased) nor in a further 100 chronic schizophrenics
and 100 nondemented controls. Nonetheless, the position of the mutation at a
critical portion of the APP gene 4 codons removed from the site of 3 Alzheimer
mutations suggests possible significance. The conclusion that the ala713-to-val
substitution in APP is causally related to schizophrenia was refuted by Mant et al.
(1992) who conducted an analysis of linkage between schizophrenia and APP
markers as well as single-strand conformation analysis of exon 17 of the APP
gene in schizophrenic subjects; it was also refuted by Carter et al. (1993) who did
DGGE analysis in 104 unrelated schizophrenic subjects. In studies of 86
unrelated chronic schizophrenics who had a first-degree relative with chronic
schizophrenia or chronic schizoaffective disorder, Coon et al. (1993) likewise
were unable to find additional cases with the codon 713 mutation.
In 2 out of 12 AD patients, in 1 out of 60 non-AD patients, and in 1 out of
30 healthy persons, Balbin et al. (1992) found a
C-to-T transition at nucleotide 2124 in exon 17 of the APP gene. The mutation
was silent at the protein level. The mutation could be used as a marker for
linkage studies involving the APP gene; whether it represented a risk factor for
the development of AD required further study.
In 2 large Swedish families linked by genealogy and containing multiple cases
of Alzheimer disease, Mullan et al. (1992) found a
double mutation in exon 16: 2 nucleotide transversions, G to T and A to C, were
observed in affected persons at codons 670 and 671, respectively. These changes
predicted lysine to asparagine and methionine to leucine substitutions in the
intact protein. Mullan et al. (1992)
suggested that this mutation, which occurs at the amino terminal of
beta-amyloid, may be pathogenic because it occurs at or close to the
endosomal/lysosomal cleavage site of the molecule. Linkage analysis showed the
mutation to be linked to the disease with a lod score of 4.36 with no
recombination. Citron et al. (1992) reported
that cultured cells that express an APP cDNA bearing this double mutation
produce 6 to 8 times more amyloid beta-protein than cells expressing the normal
APP gene. They showed that the met596-to-leu mutation was principally
responsible for the increase. (MET596LEU in the APP695 transcript is the
equivalent of MET671LEU in the APP770 transcript which was the basis of the
numbering system used by Mullan et al. (1992).) These
findings established a direct link between an FAD genotype and the
clinicopathologic phenotype.
Citron et al.
(1994) conducted blinded analyses of beta-APP metabolism in primary skin
fibroblasts from affected members of a Swedish FAD pedigree and their unaffected
sibs or spouses. These fibroblasts continuously secreted a homogeneous
population of beta-amyloid molecules starting at asp-1 (D672 of beta-APP). Citron et al.
(1994) found a consistent and significant elevation of approximately 3-fold
of beta-amyloid release from all biopsied skin fibroblasts bearing the FAD
mutation. No significant alterations of other metabolic derivatives of beta-APP
were detected. The elevated beta-amyloid levels were found in cells from both
patients with clinical Alzheimer disease and presymptomatic subjects, thus
indicating that it is not a secondary event and may play a causal role in the
development of the disease. Haass et al. (1995) showed
that the increased production of amyloid-beta peptide associated with the
'Swedish mutation' (actually the Swedish double mutation) results from a
cellular mechanism which differs substantially from that responsible for the
production of amyloid-beta peptide from the wild type gene. In the latter case,
A-beta generation requires reinternalization and recycling of the precursor
protein. In a case of the Swedish mutation, the N-terminal beta-secretase
cleavage of A-beta occurs in Golgi-derived vesicles, most likely within
secretory vesicles. Therefore, this cleavage occurs in the same compartment as
the alpha-secretase cleavage, which normally prevents A-beta production,
explaining the increased A-beta generation by a competition between alpha- and
beta-secretase.
In 2 lines of transgenic mice expressing human APP(751) containing mutations
known to cause early-onset familial Alzheimer disease, Sturchler-Pierrat et al.
(1997) observed pathologic features reminiscent of AD. The degree of
pathology depended on expression level and specific mutations. A 2-fold
overexpression of human APP with the Swedish double mutation at positions 670 to
671 combined with the V717I mutation (104760.0002)
caused amyloid-beta deposition in neocortex and hippocampus of 18-month-old
transgenic mice. The deposits were mostly of the diffuse type; however, some
congophilic plaques could be detected. In mice with 7-fold overexpression of
human APP harboring the Swedish mutation alone, typical plaques appeared at 6
months, which increased with age and were Congo Red-positive at first detection.
These congophilic plaques were accompanied by neuritic changes and dystrophic
cholinergic fibers. Furthermore, inflammatory processes indicated by a massive
glial reaction were apparent. Most notably, plaques were immmunoreactive for
hyperphosphorylated tau, reminiscent of early tau pathology. The
immunoreactivity was found exclusively in congophilic senile plaques of both
transgenic lines. In the higher expressing line, elevated tau phosphorylation
could be demonstrated biochemically in 6-month-old animals and increased with
age. These mice displayed major features resembling those of AD pathology and
supported a central role of amyloid-beta in the pathogenesis of the disease.
In a study of 130 early-onset AD patients from hospitals throughout France,
Carter et al.
(1992) found 1 patient with 2 G-to-A transitions in the APP gene: one at
codon 713 and the other at codon 715. These resulted in an ala713-to-thr
missense substitution and a silent change at val715. The 713 mutation changes
residue 42 of the beta-amyloid protein, considered to be the penultimate or
terminal amino acid of this molecule, and thus could potentially alter both
endosomal/lysosomal cleavage and the C-terminal sequence of the resulting
beta-peptide. The double mutation was present also in 4 healthy sibs and a
paternal aunt who was also healthy at age 88. (The ala713-to-val mutation found
in a schizophrenic patient (104760.0006)
involves the same residue.) This experience may represent reduced penetrance;
additional environmental factors may be necessary for expression of the disorder
or an independent genetic factor absent in the affected sib may suppress amyloid
formation in the unaffected members of the kindred.
Peacock et al.
(1994) used reverse transcription-polymerase chain reaction, denaturing
gradient gel electrophoresis, and direct DNA sequencing to analyze APP exons 16
and 17 from patients with histologically confirmed Alzheimer disease. (Amyloid
plaques in Alzheimer disease contain beta-amyloid, encoded by portions of exons
16 and 17 of the APP gene.) In a patient with late-onset Alzheimer disease, they
found a novel point mutation, a C-to-G transversion at nucleotide 2119 (770 in
the mRNA transcript). The substitution deleted a BglII site and substituted
aspartate for glutamic acid at codon 665. Hitherto, no evidence had been
forthcoming that APP mutations are involved in late-onset or sporadic Alzheimer
disease. The proposita had died at age 92. A sister had died with dementia
between 80 and 85 years of age. The same mutation was present in a nondemented
relative older than 65 years. Thus, although the mutation was not found in 40
control subjects and 127 dementia patients, its relationship to Alzheimer
disease remains uncertain.
All the families with AD caused by APP mutations had disease onset between 45
and 60 years of age, most typically with an onset in the mid-fifties. Eckman et al.
(1997) reported a family with mean onset age of approximately 53 years in
which they found an ile716-to-val mutation (I716V). Cells transfected with cDNAs
bearing this mutation produced more of A-beta-42(43) protein than those
transfected with wildtype APP. This effect was additive with that of the
previously reported APP V717I (104760.0002)
mutation.
Ancolio et al.
(1999) identified a novel beta-amyloid precursor protein mutation, val715 to
met (V715M), that cosegregated with early-onset Alzheimer disease in a pedigree.
Unlike previously reported familial AD-linked APP mutations, overexpression of
V715M in human HEK293 cells and murine neurons reduced total A-beta production
and increased the recovery of the physiologically secreted product, APP-alpha.
The V715M mutation significantly reduced A-beta-40 secretion without affecting
A-beta-42 production in HEK293 cells. However, a marked increase in N-terminally
truncated A-beta ending at position 42 was observed, whereas its counterpart
ending at position 40 was not affected. These results suggested that, in some
cases, familial AD may be associated with a reduction in the overall production
of A-beta but may be caused by increased production of truncated forms of A-beta
ending at position 42. This family with the V715M mutation was also reported by
Campion et al.
(1999), the same family having been ascertained through a population-based
survey of early-onset Alzheimer disease.
Kamino et al. (1992) described a glu22-to-gly (E22G) missense mutation in a family with cerebroarterial amyloidosis. The mutation resulted from an A-to-G transition in codon 693 and was referred to as the 'Arctic mutation' by Miravalle et al. (2000).
Miravalle et al. (2000) stated that this is 1 of 3 mutations in the same codon (693) of the APP gene that results in cerebroarterial amyloidosis.
Robakis et al. (1987); Tanzi et al. (1987)
Victor A. McKusick - updated : 9/26/2000
Ada Hamosh - updated :
7/10/2000
Victor A. McKusick - updated : 1/4/2000
Victor A. McKusick -
updated : 9/24/1999
Ada Hamosh - updated : 7/7/1999
Stylianos E.
Antonarakis - updated : 5/21/1999
Victor A. McKusick - updated :
4/13/1999
Victor A. McKusick - updated : 2/3/1999
Victor A. McKusick -
updated : 1/26/1999
Victor A. McKusick - updated : 1/26/1999
Victor A.
McKusick - updated : 11/2/1998
Orest Hurko - updated : 10/23/1998
Victor
A. McKusick - updated : 10/22/1998
Victor A. McKusick - updated :
6/12/1998
Victor A. McKusick - updated : 2/24/1998
Victor A. McKusick -
updated : 1/13/1998
Victor A. McKusick - updated : 11/20/1997
Victor A.
McKusick - updated : 2/3/1997
Moyra Smith - updated : 1/23/1997
Moyra
Smith - updated : 10/3/1996
Moyra Smith - updated : 8/21/1996
Orest Hurko
- updated : 5/8/1996
Moyra Smith - updated : 3/7/1996
Victor A. McKusick : 12/15/1986
mcapotos : 10/6/2000
mcapotos : 10/4/2000
terry : 9/26/2000
alopez :
7/12/2000
terry : 7/10/2000
mcapotos : 1/12/2000
mcapotos :
1/11/2000
terry : 1/4/2000
carol : 11/24/1999
alopez :
10/26/1999
terry : 9/24/1999
alopez : 7/8/1999
alopez :
7/7/1999
alopez : 7/7/1999
terry : 7/7/1999
mgross :
5/24/1999
mgross : 5/21/1999
carol : 5/13/1999
carol :
4/13/1999
terry : 4/13/1999
mgross : 3/16/1999
carol :
2/12/1999
terry : 2/3/1999
carol : 1/29/1999
carol : 1/26/1999
terry
: 1/26/1999
carol : 11/9/1998
terry : 11/2/1998
carol :
10/23/1998
alopez : 10/22/1998
terry : 10/22/1998
terry :
6/12/1998
alopez : 2/25/1998
terry : 2/24/1998
mark :
1/16/1998
terry : 1/13/1998
terry : 11/21/1997
terry :
11/20/1997
alopez : 7/9/1997
mark : 2/3/1997
terry : 2/3/1997
mark :
1/23/1997
mark : 1/23/1997
terry : 1/23/1997
mark : 11/18/1996
terry
: 11/14/1996
jamie : 10/25/1996
mark : 10/3/1996
mark :
8/21/1996
terry : 8/20/1996
terry : 6/21/1996
mark : 6/20/1996
mark
: 6/18/1996
terry : 6/13/1996
mark : 5/8/1996
terry : 5/2/1996
mark
: 3/7/1996
terry : 3/7/1996
mark : 2/23/1996
mark : 2/16/1996
mark :
2/15/1996
terry : 2/27/1995
carol : 1/20/1995
jason :
6/14/1994
mimadm : 4/19/1994
warfield : 4/6/1994
carol :
12/10/1993
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