1
A Brief Introduction to the History
of the β-Amyloid Protein (Aβ) of
Alzheimer’s Disease
David H. Small and Colin J. Barrow
Alzheimer’s disease (AD) is the most common
cause of dementia in the elderly. Typically, the dis-
ease progresses in a prolonged, inexorable manner
[1]. Patients initially show symptoms of mild cog-
nitive impairment, which may include some mem-
ory loss. As the disease progresses, more severe
memory loss occurs (e.g., retrograde amnesia)
leading to confusion and lack of orientation. The
patient is often institutionalized in this period, as it
becomes increasingly difficult for family members
to cope with the constant requirements of care. In
later stages of the disease, apathy and stupor can
occur, and the patient becomes bedridden.
The histopathology of AD is characterized by
gliosis and tissue atrophy caused by both synaptic
and neuronal loss, which are most pronounced in
the frontal and temporal cortices [2]. Proteinaceous
deposits are seen in both the intracellular and extra-
cellular compartments of the brain, typically in the
hippocampus and neocortex. The intracellular
deposits consist of neurofibrillary tangles that are
made up of paired helical filaments of a hyper-
phosphorylated form of the cytoskeletal protein tau
[3]. Extracellular amyloid plaques are found most
commonly in the hippocampus and neocortex and
may be diffuse or compact in nature [4]. Amyloid
is also deposited as cerebral amyloid angiopathy
within small- to medium-sized arterioles [5].
Although neurofibrillary tangles are associated
with a number of different types of neurodegenera-
tive disease, the presence of numerous compact or
neuritic amyloid plaques is a hallmark feature of
Alzheimer’s disease. For this reason, it may be
argued that accumulation of the β-amyloid protein
(Αβ) is a key step in the pathogenic mechanism of
Alzheimer’s disease. In contrast, although the den-
sity of neurofibrillary tangles correlates more
closely with the cognitive symptoms, it is now
commonly thought that tangles are a secondary
feature or the underlying disease process [6].
1.1 The Role of Aβ in AD
Glenner and Wong [7] first identified the major
protein component of vascular amyloid, which was
a low-molecular-weight, 4-kDa polypeptide, now
referred to as the β-amyloid protein (Αβ). Subse-
quent studies established that the same protein was
the major component of amyloid plaques [8]. The
complete amino acid sequence of Αβ led to the
identification of its precursor, the β-amyloid pre-
cursor protein (APP) [9].
APP has features of an integral type I transmem-
brane glycoprotein, with a large ectodomain con-
taining the N-terminus and a small cytoplasmic
domain containing the C-terminus (Fig. 1.1).
Multiple mRNA splicing of exons can generate sev-
eral different isoforms of APP that lack domains
homologous to Kunitz-type protease inhibitors
(KPI domain) and the OX-2 antigen as well as a
domain encoded by an exon that regulates O-linked
glycosylation by chondroitin sulfate. The Αβ
sequence itself comprises part of the ectodomain of
the protein and extends into, but not all the way
through, the transmembrane domain [9, 10].
Soon after its identification, APP was shown
to undergo ectodomain shedding by an enzyme
1
2 D.H. Small and C.J. Barrow
N c APP
β-cleavage α-cleavage
C99
γ-cleavage γ-cleavage
Aβ
aggregation
Neurotoxicity
AD
Aβ oligomer
FIGURE 1.1. Proteolytic processing of APP and the role of
Aβ in AD. APP can be proteolytically cleaved via two
different processing pathways. Cleavage by α-secretase
and γ-secretase generates C-terminal fragments known
as C83 and p3, whereas cleavage by β-secretase
(BACE1) and γ-secretase generates C99 and Aβ.
According to the amyloid hypothesis, Aβ aggregates
into amyloid fibrils or low-molecular-weight oligomers
that are neurotoxic. The resulting neurotoxicity causes
neurodegeneration and leads to dementia.
dubbed the α-secretase. The α-secretase cleaves
APP within the Αβ sequence, adjacent to lysine-16,
thereby destroying the sequence [11, 12]. Recently
studies suggest that enzymes of the ADAM family
of metalloproteases are responsible for this activity
[13, 14]. Other studies have demonstrated that
APP can also be cleaved at the N- and C-terminal
ends of the Αβ sequence by enzymes dubbed β-
and γ-secretase, respectively, to generate the full-
length Αβ sequence [15]. Amyloidogenic process-
ing by β- and γ-secretase is a normal, albeit minor,
pathway of APP processing. The β-secretase has
been unequivocally identified as an aspartyl pro-
tease termed BACE1 (an acronym for β-site APP
cleaving enzyme-1) [16–19]. The γ-secretase com-
prises a complex of several proteins including
presenilin-1, presenilin-2, Aph1, Pen2, and nicas-
trin. However, other protein components of this
complex may also exist [15].
There is considerable evidence that the accumu-
lation of Αβ in the brain is toxic to neurons and that
this toxicity underlies the neurodegeneration that
occurs in AD (Fig. 1.1) [20]. Aβ peptides are toxic
to cells in culture [21], and this toxicity is
associated with aggregation of the peptide [22].
Recent studies support the view that the most toxic
species are the low-molecular-weight, soluble
oligomers of Αβ [23].
C83
Despite many studies that have shown that Αβ
can disrupt biochemical events within neurons,
direct proof that the accumulation of Αβ is the
p3
cause of AD has been lacking. Nevertheless, evi-
dence that this is the case has slowly been accumu-
lating. Some of the strongest evidence that Αβ
accumulation is the cause, rather than an epiphe-
nomenon, of AD has come from the finding of
familial AD mutations present in the APP gene
[24]. All of these mutations have been found to
cluster around the Αβ sequence, and all of them
have so far been shown to directly or indirectly
cause an increase in forms of Αβ that aggregate
[25]. For example, although the most commonly
produced form of Αβ contains 40-amino-acid
residues (Αβ40), a minor form containing 42 residues
is also formed. This minor form aggregates into
amyloid fibrils much more readily than Αβ40 [26].
The first mutation to be identified in the APP gene,
the London mutation, involves a single base change
at codon 717, which encodes a form of APP that is
more readily cleaved to produce Αβ42. To date, at
least 10 familial AD mutations are known to occur
in APP [27].
The direct involvement of APP and Αβ in the
pathogenesis of AD is also strongly supported by
studies on transgenic mice. A number of transgenic
lines have been developed in which human APP is
expressed [28]. Many of these mice develop amy-
loid plaques. In addition, other features of AD
pathology such as neuritic dystrophy, abnormal tau
phosphorylation, gliosis, synaptic loss, and behav-
ioral abnormalities have been observed. Although
human APP mice do not develop neurofibrillary
tangles, this is probably due to differences between
mouse tau and human tau isoforms. Indeed, in
double transgenic mice expressing both mutant
human tau and APP, Αβ is seen to increase tau
deposition [29].
Mutations in the APP gene account for only a
very small percentage of all familial Alzheimer’s
disease (FAD) cases. Shortly after the identifica-
tion of the first familial AD mutation in the APP
gene, mutations were identified in two other genes,
PS1 encoding presenilin-1 and PS2 encoding
1. Brief Introduction to the History of the β-Amyloid Protein
presenilin-2, located on chromosomes 14 and 1,
respectively [30, 31]. Both presenilin proteins are
components of the γ-secretase complex, and famil-
ial AD mutations within the PS1 and PS2 genes
alter γ-secretase processing in a way that leads to
the production of more Αβ42 [32].
In general, mutations in the APP, PS1, and
PS2 genes lead to early-onset forms of AD. In
contrast, the apolipoprotein E (apoE) gene
located on chromosome 19 is a risk factor for
late-onset AD [33]. There are three forms of
apoE, termed E2, E3, and E4, encoded by three
allelic variants ε2, ε3, and ε4. The ε4 variant is a
risk factor for late-onset AD, whereas the ε2 may
be protective. Although the reason for this is still
unknown, it is undoubtedly related to Aβ pro-
duction, aggregation, or clearance from the
brain. Individuals with the ε4 allele have more
Aβ deposition within the brain [34]. In addition,
APP x apoE knockout transgenic mice develop
little amyloid deposition in their brains, unlike
normal APP mice [35]. Thus, studies on the role
of apoE in AD provide strong support for the Aβ
hypothesis.
1.2 Anti-Αβ Therapies for AD
The idea that Aβ is a primary causative agent in
AD leads inevitably to the view that an effective
therapy based on inhibiting the production, aggre-
gation, clearance, or toxicity of Aβ may be achiev-
able. One of the most promising but controversial
approaches in recent years has been Αβ immuniza-
tion. Studies show that in transgenic mice, immu-
nization with Αβ42 leads to the generation of
an immune response [36]. Anti-amyloid antibod-
ies bind to amyloid plaques and appear to facilitate
their removal from the brain, leading to an
improvement in cognitive performance compared
with nonimmunized control animals. Unfortu-
nately, clinical trials of this approach in humans
have been halted because a small percentage of
individuals immunized with Αβ have developed a
severe meningoencephalitis [37]. Nevertheless,
there is some evidence that patients who develop a
strong immune response to Αβ without the associ-
ated brain inflammation may benefit from this
approach [38].
3
1.3 Current Status of the Aβ
Hypothesis of AD
There is now very strong evidence that accumula-
tion of oligomeric or fibrillar Αβ in the brain is a
key event in the pathogenesis of AD. Perhaps the
most important unresolved question is the mecha-
nism by which Αβ causes its neurotoxic effect. It is
also unclear what form of aggregated Αβ is the
most neurotoxic. Another major question is how
many unidentified genetic risk factors there are and
how these risk factors affect Αβ production, aggre-
gation, or clearance. If anti-Αβ therapies can be
used successfully for the treatment of AD, then the
remaining concerns about the role of Αβ in the
pathogenesis of AD will have been answered.
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