PERSPECTIVES
The properties of attractor neural net-
OPINION
Alzheimer’s disease and Aβ toxicity:
from top to bottom
David H. Small, Su San Mok and Joel C. Bornstein
Evidence implicating the β-amyloid protein
(Aβ) in the pathogenesis of Alzheimer’s
disease has steadily accumulated. However,
the mechanism by which Aβ causes
dementia is unknown. Here we argue that a
more integrated, top–down approach to
brain function is needed to assess the role of
Aβ in Alzheimer’s disease, and that more
attention should be paid to the effects of Aβ
on synaptic function rather than on cell death.
Alzheimer’s disease (AD) is a progressive
neurological disorder that is characterized
by memory loss and confusion. There is
good evidence indicating that the accumula-
tion of the β-amyloid protein (Aβ) is a pri-
mary event in the pathogenesis of AD1. Aβ is
a 4-kDa polypeptide derived by the prote-
olytic cleavage of the Aβ precursor protein
(APP)2. The main form of Aβ contains 40
amino-acid residues. However, carboxy-ter-
minally extended species that contain 42 or
43 residues (‘long Aβ’) are also produced2.
These long forms of Aβ aggregate more
readily than the 40-amino-acid peptide. It is
generally believed that aggregated Aβ is the
agent that is responsible for disease progres-
sion, as the accumulation of aggregates is
toxic to the brain1. The fact that many famil-
ial AD mutations increase the production of
long Aβ (REF. 3) provides strong support for
this idea.
One of the central unanswered questions in
AD is how Aβ accumulation in the brain caus-
es cognitive decline. This question has generally
been addressed by using the ‘bottom–up’ strat-
egy. In other words, the direct biochemical
effects of Aβ are examined in vitro with the
hope that they will help us to elucidate the
mechanism of neurotoxicity. This approach
has led to the identification of numerous bio-
chemical pathways and mechanisms that are
modified by Aβ (FIG. 1). However, it has been
difficult to determine which of these pathways
are the most important in the onset of AD, and
which should be targeted for the development
of new therapeutic agents. It seems unlikely
that all the biochemical effects of Aβ are associ-
ated with dementia and, in fact, it is not clear
that cell death is the most relevant factor4.
NATURE REVIEWS | NEUROSCIENCE
In this article, we argue that a more inte-
grated approach to brain function is needed
to assess the role of Aβ in AD. Specifically,
we suggest that a ‘top–down’ approach
derived from computational neuroscience5
can provide clues to identify biochemical
pathways that are central to AD and worth
targeting for therapy.
A top–down approach
A key to understanding the actions of Aβ in
AD is to determine how this protein affects
the neuronal networks in which memories
are stored, thereby causing dementia. This
depends on an understanding of how stable
memories form within a network, and how
specific types of damage might lead to the
amnesia that is typical of AD. This type of
amnesia is characterized by difficulty in
acquiring new memories, the sparing of
established memories early in the disease, and
the later, gradual loss of these memories6.
The pioneering work of Hopfield7,8 showed
that interconnected networks of model neu-
rons can form associative memories if the
strength of synaptic connections between
these neurons changes as a result of prior
activity. In these computational models, asso-
ciative memories are coded by the strength of
individual synaptic connections — the ampli-
tudes of synaptic potentials — between differ-
ent neurons, and are relatively insensitive to
the loss of individual cells. Furthermore, indi-
vidual neurons can be involved in several
memories, a finding that has been confirmed
in electrophysiological studies9,10.
Networks of this type have been termed
attractor neural networks11. They learn
because any given input pattern leads to a
strengthening of specific synapses on some
neurons in the network. If an input is repeat-
ed, the synaptic strengthening will ultimately
impose a pattern of synaptic strengths onto
the network, which ensures that inputs similar
to the training input will produce the same
output pattern. The network will be ‘attracted’
to a common output pattern for related
inputs, so that part of a memory can be used
to recall the whole, a characteristic of explicit
memory that is specifically vulnerable in AD.
© 2001 Macmillan Magazines Ltd
works can provide significant clues to poten-
tial sites of action for Aβ. For example, loss
of both neurons and synapses are prominent
features in post-mortem studies of AD12–14.
However, analyses of attractor networks that
feature a loss of neurons and the consequent
loss of synapses indicate that neuronal loss
does not account, by itself, for the properties
of the amnesia characteristic of AD15,16. By
contrast, a loss of synapses, without an asso-
ciated loss of neurons, can account for all the
features of AD, assuming that a mechanism
that acts to keep the average firing of each
neuron constant over time is also operat-
ing15,16. Recent physiological studies have
indicated that such a mechanism (synaptic
scaling, see below) is widespread in the ner-
vous system17–19. The loss of synapses in AD
is substantially greater than could be
explained by the loss of neurons12, which
indicates that a deficit of synapses might be a
primary problem in the early phases of AD.
The implication of these studies is that the
biochemical targets of Aβ leading to cell
death (FIG. 1) could be less important for
early treatment than those that produce
selective toxic effects on synapses.
However, studies of attractor networks
indicate that the dementia that is character-
istic of AD might actually precede any overt
loss of synapses or neurons. For example,
studies of this sort indicate that synapse-spe-
cific changes in synaptic strength due to pre-
or postsynaptic activity — such as long-term
potentiation (LTP) or long-term depression
(LTD) — cannot, by themselves, account for
the formation of several stable memories
within one network19–22. This is because
inputs that excite overlapping parts of the
network will tend to be attracted to the
‘strongest’ pattern of synapses, strengthening
it and swamping newer or weaker memo-
ries. Studies of attractor networks also indi-
cate that synaptic scaling can compensate for
this phenomenon, thereby allowing a net-
work to store many stable memories17–22.
Synaptic scaling is a slower homeostatic
mechanism by which the strength of all
synaptic input to a neuron is regulated by
the overall activity of that neuron over time.
High levels of firing lead to all synapses on a
neuron becoming weaker, whereas low levels
of firing increase the strength of these
synapses. These changes are independent of
the synapse-specific mechanisms of LTP and
LTD, and act by preventing already strong
synapses from becoming even stronger.
Synaptic scaling seems to result, at least in
part, from the insertion and removal of the
α-amino-3-hydroxy-5-methyl-4-isoxazole
VOLUME 2 | AUGUST 2001 | 5 9 5
PERSPECTIVES

Neurotoxicity
Astrocyte Peroxynitrites Neuron
85

iNOS NO 58
Na+/K+ ATPase
Aβ + Cu2+ p35/cdk5
NFκB Ion channel 56,57
59
Calpain
55
39,40
Ca2+ Ca2+
86 L-VGCC 41–43 p25/cdk5

ROS 54

Other 65
TNFα IL1β ATP
cytokines
62,63
p75NTR
60
APP
86 68
ER stress Caspase 12
NFκB RAGE
77
66,67
FAS/TNFR/etc FADD Caspase 8
79 87
Tyrosine ERAB
kinases 76 Apoptosis/
Aβ necrosis
64
Endosomal lysosomal
Class A 82–84 modification
scavenger 51–53
receptor 54
77 78 ROS
RAGE
78
cfms m-CSF NFκB
61
Aβ Binding to membrane

80,81
74,75
Other proteins?
cdk4/6 Rb Bax
E2F1
70–72
c-jun
73 Caspase 3
JNK Caspase 2 Other caspases?
69
NO
ROS Peroxynitrite
cytokines TNFR
Microglia RNS
e.g. TNFα
Neurotoxicity
Figure 1 | Pathways in neurons, astrocytes and microglia that are implicated in β-amyloid toxicity. The numbers shown in the figure refer to the
appropriate references in the bibliography. APP, Aβ precursor protein; Aβ, β-amyloid; Bax, B-cell-leukemia/lymphoma-2-associated X protein; cdk, cyclin-
dependent kinase; cfms, m-CSF receptor; E2F1, E2F transcription factor 1; ER, endoplasmic reticulum; ERAB, endoplasmic-reticulum-associated binding
protein; FADD, FAS-associated protein with death domain; FAS/TNFR, FAS/tumour necrosis factor receptor; IL1β, interleukin 1β; iNOS, inducible nitric oxide
synthase; JNK, c-Jun N-terminal kinase; L-VGCC, L-type voltage-gated Ca2+ channel; m-CSF, macrophage-colony-stimulating factor; NFκB, nuclear factor κB;
NO, nitric oxide; p25, calpain cleavage product of p35; p35, cyclin-dependent kinase 5 regulatory sumit; p75NTR, 75 kDa neurotrophin receptor; RAGE, receptor
for advanced glycation end products; Rb, retinoblastoma protein; RNS, radical nitrogen species; ROS, radical oxygen species; TNFα, tumour necrosis factor α.

propionic acid (AMPA) subtype of gluta-
mate receptor into subsynaptic mem-
branes17–19. The expression of this class of
receptor is indeed altered in AD23, indicating
that the mechanisms regulating synaptic
scaling might be a target of Aβ in AD.
Computational studies have also pointed
to a second mechanism by which the forma-
tion of memories within a network can be
stabilized. This mechanism depends on the
balance between LTP and LTD induced at dif-
ferent synapses on the same neuron by specif-
ic patterns of pre- and postsynaptic firing.
Each time a neuron fires, there will be an
increment of LTP at some synapses and LTD
at others, keeping the overall strength of the
inputs to the neuron relatively constant.
However, computational studies indicate that,
unless the ratio of these two processes is with-
in a narrow range, the number of memories
that can be stored within a network is severely
limited and independent of the size of the
network20. So, these theoretical studies indi-
cate that a selective change in either LTP or
LTD, resulting from Aβ accumulation, would
prevent the conversion of short-term memo-
ries into stable long-term memories — that is,
anterograde amnesia. This would be seen,
regardless of whether the process affected is
enhanced or depressed by Aβ.
In addition to the biochemical pathways
that mediate LTP and LTD24–26, the balance
of LTP and LTD in neocortical and hip-
pocampal pyramidal cells depends on two
factors. First, the relative timing of pre- and
postsynaptic activity at individual synaps-
es27,28, and second, the entry of Ca2+ during
temporally associated dendritic action
potentials and synaptic potentials.
The timing of pre- and postsynaptic
activity depends on dendritic action poten-
tials evoked in the postsynaptic neuron by
the generation of action potentials at the
axon hillock29. These have been identified in
both in vitro29 and in vivo studies30.
Electrophysiological analyses in neocortical
slices indicate that, if a presynaptic action
potential precedes a dendritic action poten-
tial by a few milliseconds, then LTP is
induced at that synapse27. If it trails a den-
dritic action potential by the same margin,
then LTD is induced27. This spike-timing-
dependent plasticity can form a stable
memory system28,31, but anything that pro-
duces a change in dendritic length would
upset this stability by altering timing. The
Aβ deposits that are characteristic of AD

596 | AUGUST 2001 | VOLUME 2 www.nature.com/reviews/neuro

© 2001 Macmillan Magazines Ltd

modify the shape and length of pyramidal
cell dendrites32, and biophysically realistic
simulations indicate that these changes are
sufficient to modify the relative timing of
pre- and postsynaptic action potentials32.
So, computational studies indicate that the
effects of Aβ on dendritic remodelling — a
continuous process in vivo33 — could be of
considerable importance in AD.
The entry of Ca2+ during temporally asso-
ciated dendritic action potentials and synap-
tic potentials is a second key factor. This is
crucial for the development of both LTP and
LTD, and depends, in large part, on L-type
Ca2+ channels29,34, which are presumed to be
located on dendritic spines35. Aβ has been
shown to stimulate this type of Ca2+ channel
(FIGS 1 and 2), either by a direct action on the
channel itself or through another receptor
(such as the α7 nicotinic acetylcholine recep-
tor (α7 nAChR) — see below). So, distur-
bances in Ca2+ handling in dendrites and
spines could also be an important locus of
Aβ action.
How could Aβ influence plasticity?
As discussed extensively by Arendt36, there is
substantial evidence that Aβ has selective
actions on synapses. Furthermore, Phinney
et al.37 have documented aberrant axonal
sprouting and ectopic terminal formation in
APP transgenic mice. Nevertheless, the
mechanism by which Aβ affects synaptic
plasticity remains a matter of conjecture.
Neural computation studies indicate the
type of physiological change that could
cause AD-type amnesia, but they do not
indicate which of these are most important
in vivo. However, computational studies do
point to a number of questions that can be
tested experimentally. For example, what are
the effects of Aβ on the balance between LTP
and LTD in a single neuron? What effect
does Aβ have on dendritic remodelling in
vivo? What is the effect of Aβ on AMPA
receptor recycling? These questions remain
unanswered, and should be the focus of
future research.
Not only do neural computation studies
point to promising experiments, but they also
indicate that certain known actions of Aβ
might be important for the cognitive impair-
ments in AD. For example, altering Ca2+ levels
through L-type Ca2+ channels on dendritic
spines34,35 would be expected to influence
LTP29,34 and dendritic remodelling38 (FIG. 2).
Several studies have shown that Aβ can pro-
mote Ca2+ entry through L-type channels39–43,
although the mechanism by which this
occurs is still unknown. The extracellular-sig-
nal-regulated kinase/mitogen-activated pro-
NATURE REVIEWS | NEUROSCIENCE
AChE inhibitors
AChE Choline + acetate
ACh Aβ
Ca2+
45–49 41–43 Ca2+
α7 L-VGCC
Ca2+
nAChR
43
LTP
AChE
MAP kinase 25
44
Cytoskeletal remodelling
and tau phosphorylation
Dendritic spine
Figure 2 | Effects of β-amyloid on pathways
that control synaptic plasticity in dendrites.
β-Amyloid (Aβ) can alter Ca2+ concentrations in
dendrites, either by binding directly to α7 nicotinic
acetylcholine receptors (α7 nAChRs), or by
interacting directly or indirectly with L-type
voltage-gated Ca2+ channels (L-VGCC). Increased
intracellular Ca2+ could influence long-term
potentiation (LTP) or long-term depression (LTD)
directly; alternatively, by activating extracellular-
signal-regulated kinase/mitogen-activated protein
kinase (ERK/MAP kinase), it might affect LTP and
LTD, and alter dendritic architecture through
cytoskeletal remodelling. The numbers shown in
the figure refer to the corresponding references in
the bibliography. ACh, acetylcholine; AChE,
acetylcholinesterase.
tein kinase (ERK/MAP kinase) cascade is also
known to be an important signalling pathway
for synaptic plasticity25, and increased
ERK/MAP kinase is associated with tau phos-
phorylation and the cytoskeletal abnormali-
ties found in dystrophic neurites in AD44.
Recently, Aβ has been shown to activate the
MAP kinase cascade in hippocampal neurons
through the α7 nAChR45. Aβ binds very
strongly to this receptor46–48, although the
precise effect of the interaction between Aβ
and α7 nAChRs might be complex49. For
example, Aβ could partially block receptor
activation, but it might also inhibit receptor
desensitization49 (FIG. 2). As nicotinic agonists
protect neurons from Aβ-induced neurotoxi-
city50, the therapeutic effects of cholinesterase
inhibitors in AD patients could be due to
increased nicotinic receptor activation (FIG. 2).
Testing the role of Aβ in AD
Aβ undoubtedly has multiple effects on neu-
rons. However, not all of these effects will
contribute to the cognitive changes seen in
© 2001 Macmillan Magazines Ltd
PERSPECTIVES
AD, and not all will be worthwhile targeting
for therapy. The results of neural network
studies provide insights into how memories
can be stored, and give us important clues to
the possible ways in which Aβ could act to
deteriorate memory storage. Future studies
should be aimed at testing the predictions
generated by computational studies. Even
though the discipline of computational neu-
roscience is still in its infancy, certain concepts
are already clear. For example, theoretical
studies show that the effects of Aβ on cogni-
tion are unlikely to be associated with cell
loss. The theory also indicates that the best
targets for therapeutic intervention are mech-
anisms that alter synaptic plasticity.
Ultimately, however, the proof of any hypoth-
esis concerning the role of Aβ in AD will rest
on the therapeutic efficacy of drugs that
specifically target the proposed mechanisms.
David H. Small*, Su San Mok* and Joel C.
Bornstein‡ are at the Departments of *Pathology
and ‡Physiology, The University of Melbourne,
Victoria 3010, Australia.
Correspondence to D.H.S.
e-mail: davidhs@unimelb.edu.au
Links
DATABASE LINKS Alzheimer’s disease | APP |
α7 nAChR | ERK/MAP kinase | tau | Bax | cdk |
E2F1 | ERAB | FADD | FAS/TNFR | IL1β |
iNOS | JNK | L-VGCC | m-CSF | NFκB | p35 |
p75NTR | RAGE | Rb | TNFα
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