The Monomer State of Beta-Amyloid: Where the Alzheimer's Disease Protein Meets Physiology

Freund & Pettman, U.K. Reviews in the Neurosciences 21, 83-93 (2010)

VOLUME 21, NO. 1, 2010 67

The monomer state of beta-amyloid: where the Alzheimer’s

disease protein meets physiology

M.L. Giuffrida1,2

, F. Caraci2, P. De Bona

3, G. Pappalardo

4, F. Nicoletti

5,6, E. Rizzarelli

3, A. Copani

2,4

1I.N.B.B. Fellowship,

2Department of Pharmaceutical Sciences,

3Department of Chemical Sciences,

University of Catania, and 4Institute of Biostructure and Bioimaging, National Research Council,

Viale Andrea Doria, Catania 95125, Italy; 5Department of Human Physiology and Pharmacology,

University of Rome “La Sapienza”, Piazzale Aldo Moro, Rome 00185, Italy; 6Instituto Neurologico

Mediterraneo, Neuromed, Località Camerelle, Pozzilli 86077, Italy

SYNOPSIS

One hundred years of study have identified

beta-Amyloid (Aβ) as the most interesting

feature of Alzheimer’s disease (AD). Since the

discovery of Aβ as the principal component of

amyloid plaques, the central challenge in AD

research has been the understanding of Aβ

involvement in the neurodegenerative process of

the disease. The ability of Aβ to undergo

conformational changes and subsequent aggre-

gation has always been a limiting factor in

finding out the activities of the peptide.

Extensive research has been carried out to

study the molecular mechanisms of amyloid

self-assembly. The finding that soluble Aβ

concentrations in the brain are correlated with

the severity of AD, whereas fibrillar density is

not /40,42/, has pointed attention toward the

oligomeric forms of Aβ, which are generally

considered the most toxic and, therefore, the

most important species to be addressed. Despite

great efforts in basic AD research, none of the

currently available treatments is able to treat

the devastating effects of the disease, leading to

the consideration that there is more to reason

_____________________________ Accepted: February 10, 2010

Address for correspondence:

A. Copani

Department of Pharmaceutical Sciences

University of Catania, Viale Andrea Doria 6, Catania

95125, Italy; phone: +39-095-7384212.

e-mail: [email protected]

than just Aβ production and aggregation. Here

we summarize the emerging evidence for the

physiological functions of Aβ, including our

recent demonstration that Aβ monomers are

endowed with neuroprotective activity, and

propose that Aß aggregation might contribute

to AD pathology through a “loss-of-function”

process. Finally, we discuss the current

therapeutics targeting the cerebral load of Aβ

and possible new ones aimed at preserving the

biological functions of Aβ.

KEYWORDS

Aβ monomers, insulin/IGF-1 receptor, excitotoxicity,

neuroprotection, aggregation inhibitors

SOLUBLE AΒ OLIGOMERS AS INITIATING

FACTORS IN ALZHEIMER’S DISEASE

In the controversial literature about

Alzheimer’s disease (AD), a predominant idea that

seems to be universally accepted refers to the

crucial role of Aβ in the pathogenesis of the

disease. The “amyloid cascade hypothesis” can be

considered the first effort in combining and

harmonizing the great amount of findings on Aβ in

AD /25/. The hypothesis summarizes the

sequential steps occurring during the aggregation

process of Aβ, with the earliest event of the

cascade, being the increased production of Aβ

monomers that arise either from missense

mutations in specific genes linked to the familial

form of the disease or from multifactor causes in

mailto:[email protected]

M.L. GIUFFRIDA ET AL.

REVIEWS IN THE NEUROSCIENCES

84

the sporadic form of AD. The change of Aβ

folding is another crucial event that influences the

aggregation properties of the peptide, and gives

rise to the formation of soluble Aβ aggregates (i.e.,

oligomers). Soluble Aβ oligomers correlate better

with dementia than insoluble fibrillar deposits /40/,

suggesting that peptide oligomers may represent

the primary neurotoxic species in AD. The

neurotoxicity of Aβ oligomers has been confirmed

by distinct experimental approaches, including the

use of synthetic or native Aβ peptides, cell culture

systems over-expressing the amyloid precursor

protein (APP) from which Aβ is derived, and APP

transgenic mice /75,38/.

Today, diffusible oligomers of Aβ are

considered metastable neurotoxic molecules that

exist for prolonged periods without conversion to

fibrillar structures. Therefore, attention has been

focused on Aβ oligomeric species to elucidate the

underlying mechanism of neuronal degeneration.

Many different types of assembly forms of

synthetic Aβ, including protofibrils (PFs), annular

structures, paranuclei, Aβ-derived diffusible

ligands (ADDL), and globulomers have been

described over the last two decades /71/. In

particular, ADDLs have been shown to inhibit

hippocampal long-term potentiation /77/ and to

cause death in different culture systems /33,29/.

The pathogenic relevance of natural Aβ

oligomers is supported by the finding that their

formation is increased by expressing AD-causing

mutations within APP or presenilin genes in

recombinant cells /83/. Moreover, putative ADDL-

like oligomeric assemblies have been isolated from

post-mortem AD brains and their presence

correlates with memory loss /21/. Natural

oligomers of human Aβ are acutely toxic on

synaptic functions when micro-injected in living

rats /75/ or added in vitro to hippocampal slices

/73/. In rats, Aβ oligomers have also been shown

to interfere rapidly and reversibly with the memory

of a learned behavior /30/. Noteworthy, the

evidence that Aβ immunotherapy neutralizes the

synapto-toxic effects of soluble oligomers /30/ has

led to the notion that antibody-mediated

inactivation of Aβ oligomers might be a

therapeutic strategy for early AD /60/.

AΒ AS A MODULATOR OF SYNAPTIC

ACTIVITY: THE UNKNOWN SPECIES

The production of the Aβ through the endo-

proteolytic cleavage of APP is a physiological

process that occurs normally in neuronal cells /8/.

After production, Aβ is exported outside the brain

by the low density lipoprotein receptor related

protein-1 (LRP-1). The amount of Aβ synthesized

outside of the brain is instead transported inside via

the receptor for advanced glycation end-products

/41/. The tightly regulated bidirectional trafficking

of Aβ across the blood brain barrier suggests a

biological role of the protein for which the

production and removal of the peptide must be

maintained into a specific range of concentrations.

Accordingly, several metalloproteases, including

neprilysin, insulin-degrading enzyme (IDE) and

endothelin converting enzymes, have been reported

to act in Aβ clearance /16,58/.

During the past decade, few physiological

activities have been proposed for the peptide. More

recently, the use of transgenic mice has provided a

further hint toward this concept. β-Amyloid

precursor protein cleavage enzyme (BACE 1)

knock-out mice, which lack Aβ formation, have

behavioral deficits /26/ and synaptic dysfunctions

/49,76/, including a reduced activity-dependent

strengthening of presynaptic release at mossy fiber

synapses /76/.

Similar to BACE 1 knock-out, APP null

mutant mice show an impaired formation of LTP

and, as a consequence of this synaptic impairment,

they have reduced learning and memory /45,10,

64/. These finding might well be related to the loss

of function of either BACE 1 or APP, rather than

to the missing production of Aβ. Interestingly

enough, however, the transgenic approach

strengths the older finding that physiological Aβ

production sustains survival in cultured neurons

/56/. Along this line is the demonstration that

picomolar concentrations of synthetic Aβ, which

are likely to approximate the endogenous level of

the peptide, enhance synaptic plasticity and

memory in the hippocampus /57/. In the same

system, high nanomolar concentrations of Aβ led

to the well known impairment of synaptic

functions /57/, suggesting that the concentration

MONOMER STATE OF BETA-AMYLOID

VOLUME 21, NO. 1, 2010

85

level of the peptide is crucial for its physiological

activity.

Several lines of evidence converge to indicate

that Aβ is released in normal brains during

synaptic activity. Kamenetz and colleagues /28/

first reported that Aβ is secreted from healthy

neurons in response to neuronal activity, and in

turn, can down-regulate excitatory synaptic

transmission. This negative feedback loop, in

which neuronal activity promotes Aβ production

and Aβ decreases synaptic activity, would provide

a physiological homeostatic mechanism to

maintain the levels of neuronal activity. Recently,

the regulation of the endogenous synaptic release

of Aβ has been addressed in rodent hippocampal

cells and slices /1/. This study shows that acute

increases in Aβ levels expand reversibly the

number of active synapses and the amount of

neurotransmitter released at each synapse, whereas

enduring inhibition of Aβ clearance results in a

reduction in the number of synapses. Thus, Aβ

appears to be a modulator of synaptic activity

requiring a fine balance between production and

removal. Accordingly, sequestration of endogenous

Aβ by the monoclonal antibody 4G8 disrupts

memory in adult rats, whereas hippocampal

injection of physiological concentrations of Aβ

rescues the amnesia produced by the anti-Aβ

antibody /19/.

Different from normal Aβ concentrations, the

high levels of peptide present in transgenic mice

over-expressing human APP are per se sufficient

to elicit epileptiform activity and seizure, even at

an early stage of the pathology and in the absence

of neuronal loss /52/. This Aβ–induced aberrant

neuronal activity has been suggested to trigger

compensatory inhibitory responses causally linked

to cognitive decline. In AD patients, 7% to 21% of

individuals with sporadic AD are estimated to have

at least one unprovoked clinically apparent seizure

during the illness. The relationship between this

phenomenon and AD is even stronger in the case

of autosomal dominant early onset AD /51/.

Once again, the levels of soluble Aβ may be

critical for the dual effect of Aβ at the synapse.

The discovery that Aβ binds to the 7 subunit of

nicotinic acetylcholine receptors (nAChRs) with

high affinity has provided strong support to the old

hypothesis of a cholinergic deficit responsible for

the cognitive dysfunction in AD (reviewed in /48/.

Nevertheless, whereas higher concentrations of Aβ

desensitize 7-containing nAChRs /55,35/, low

concentrations of the peptide appear to activate

pre-synaptic nAChRs /13,35/, which are responsible

for glutamate release during LTP.

Additional effects of Aβ at the synapse have

been reported as being solely disruptive and linked

to an impairment of AMPA and NMDA receptor

trafficking /67,23/, or to the disassembly of the

post-synaptic density /59/ Aβ. These and similar

studies refer to synthetic preparations of Aβ

oligomers, and clearly suggest that the concen-

trations of Aβ in the synaptic cleft affect its

aggregation state, and that differently assembled

Aβ aggregates have different effects on synaptic

activity. Nevertheless, the true identity of the Aβ

species that act as modulators of synaptic activity,

especially in the case of endogenous released Aβ

/1/ remains unclear.

AΒ MONOMER: THE NEUROPROTECTIVE

SPECIES

Based on the notion that synaptic activity

regulates the expression of gene products that are

important for neuronal survival /78/, the evidence

that Aβ can act as a synaptic modulator is per se

suggestive of a pro survival role of the peptide. One

of the first pieces of evidence supporting a

physiological role for Aβ dates back to 1989, when

the 1-28 fragment of the peptide was shown to have

neurotrophic activity /79/. The following years have

been characterized, instead, by an extensive amount

of research on the toxic effects of aggregated forms

of Aβ. Recently, emerging interest in the putative

physiological roles of Aβ has provided new

interesting data. Indirect evidence for the

implication of Aβ in the normal neuronal

metabolism can be found in several papers

published in this field. The in vitro inhibition of

either β- or γ-secretase seems to affect the viability

of cortical neurons, which are rescued by adding

picomolar concentrations of Aβ1-40/42 /56/.

The contribution of Aβ to physiological

neuronal activity is strengthened by the

observation that the addition of Aβ(1-42) to

cultured neurons enhances glucose uptake and



86

metabolism via the induction of hypoxia-inducible

factor-1 /69/. More important, indirect evidence for

a neuroprotective activity of Aβ has been recently

obtained in patients who underwent invasive

intracranial monitoring after acute brain injury.

The results provided by the authors show a strong

correlation between the Aβ levels in the cerebral

interstitial fluid and the patients’ neurological

status, with Aβ concentrations increasing when the

neurological status improves and falling when the

neurological status declines. /6/.

We recently identified the nature of the neuro-

protective effect of Aβ1-40/42, demonstrating that

the protective activity of Aβ is confined to

monomeric, low concentrated form of the peptide.

In neurons undergoing death by trophic deprivation,

synthetic Aβ(1-42) monomers had a rescuing effect

mediated by the activation of the phosphatidyl-

inositol-3-kinase (PI-3-K) pathway. The activation

of the PI-3-K pathway, which is a main surviving

path in neurons /18/, could be reconducted to the

stimulation of IGF-1 receptors and/or other

receptors of the insulin superfamily /20/.

Interestingly, Aβ1-40/42 monomers had a broad

rescuing effect that included neuroprotection against

excitotoxic cell death, a process that contributes to

several neurodegenerative diseases /14/.

A dysregulation of Insulin/IGF-1 signaling is

thought to sustain a crucial role in the pathogenesis

of AD. Some evidence indicates that insulin/IGF-1

resistance, as occurs in type 2 diabetes, is linked to

the development of late-onset forms of AD /39,61/

and alterations of both insulin receptors and IGF-1

receptors have been reported in the AD brain

/44,12/.

Zhao and co-workers have suggested that

insulin resistance in the AD brain is a response to

Aβ oligomers (ADDLs), which downregulate

neuronal surface insulin receptors /85/. On the

contrary, insulin/IGF-1 receptor activation seems

to promote the reduction of ADDLs to monomers

via the insulin-degrading enzyme (IDE) activity

/84/. According to this evidence, accumulating

toxic Aβ species impair insulin/IGF-1 signaling

that in turn will exacerbate Aβ aggregation with

ensuing neurotoxicity. Interestingly, the other way

around would be that Aβ monomers sustain

insulin/IGF-1 signaling that in turn will impede

oligomerization (Fig. 1).

We should highlight that monomers of the

arctic-mutant Aβ(1-42) do not share the same

neuroprotective properties of the Aβ40/42 peptides

/20/. Conformational studies of the different Aβ

monomers indicate that the neuroprotective Aβ40/

42 species share similar folding properties and

have similar conformational features /20/, thus

suggesting that they might bind to specific

recognition sites on the neuronal surface. Whether

Aβ40/42 bind directly to IGF1/insulin receptors

remains to be established.

CURRENT STATUS OF DISEASE-MODYFING

DRUGS IN AD AND THE POTENTIAL ROLE OF

A MONOMERS FOR DESIGNING NEW

PHARMACOLOGICAL STRATEGIES

In the process leading to oligomers formation

from APP production, many steps could potentially

be targeted for the treatment of AD. Immuno-

therapy can be considered an approach potentially

able to target the production, aggregation, and

deposition of Aβ, and anti-Aβ therapy is

considered one of the most interesting possibilities

for the development of disease-modifying drugs in

AD /36,72/. Active immunization promotes the

formation of antibodies against Aβ by stimulating

an immune response in the patient, whereas

passive immunotherapy supplies antibodies from

an exogenous source /72/. Active Aβ immuno-

therapy has been studied and validated since 1999

in AD mouse models, in which the generation of

Aβ antibodies results in the clearance of cerebral

amyloid plaques, a process dependent on

microglial phagocytosis of antibody-opsonized Aβ

deposits /63/. Aβ immunotherapy improves

cognitive deficits in AD mouse models and lowers

the plaque load in non-human primates /36/.

Unfortunately, a Phase II clinical trial of active

immunization (the AN-1792 vaccine), using full-

length human Aβ(1-42) peptide with QS-21

adjuvant, had to be stopped prematurely in 2002

because approximately 6% of patients developed

aseptic meningoencephalitis /7/. Different

mechanisms have been proposed to explain the

negative side effects of the AN-1792 vaccine trial,

including the occurrence of a T-cell recognition of

the human full-length Aβ as a self-protein, which


VOLUME 21, NO. 1, 2010

87

Fig 1: Schematic drawing of the interactions between Aβ(1-42) and the insulin/IGF-1 receptor signaling (IR/IGF-1R).

Monomeric forms of Aβ promote the activation of the insulin/IGF-1 signaling, resulting into a sustained

neuronal survival (via the activation of the PI-3K pathway) and self-maintened levels of Aβ monomers (via the

activity of the insulin-degrading enzyme -IDE- ). On the contrary, accumulating ADDLs induce the

downregulation of insulin/IGF-1 receptors that will exacerbate Aβ aggregation with ensuing neurotoxicity.

Dashed lines refer to uncharecterized mechanisms of action. Question mark refers to the unknown binding site

of Aβ monomers.

may have induced an adverse auto-immune response /81/. Data collected from patients over a period of 6 years following immunization with AN-1792 demonstrated that

the generation of anti-Aβ antibodies results in the

clearance of amyloid plaques in the AD brain, but

this clearance does not prevent progressive neuro-

degeneration /46,27/. Thus, it seems that removing

fibrillar amyloid from the brain may not be

sufficient to alter the course of AD. Furthermore,

significant aspects of AD pathology were

unaffected by vaccination, including the presence

of vascular amyloid and of hyper-phosphorylated

tau deposits /31/.

Alternative safer approaches for active

immunization are being developed, including those

using short Aβ immunogens that miss Aβ-specific

T cell epitopes (Aβ16-42) /36/.

Passive Aβ immunotherapy is being pursued

by administering monthly intravenous injections of

humanized Aβ monoclonal antibodies (i.e.,

bapineuzumab) to AD patients /62/. The results

from a phase II clinical trial indicate a potential

efficacy of bapineuzumab on cognitive functions in

APOE epsilon4 non-carriers with mild to moderate

AD, but not in APOE epsilon4 carriers (i.e.,

individuals carrying the major genetic risk factor

for AD), where this drug even favors the onset of a

vasogenic edema /62/.

Taking into consideration the role of Aβ

monomers in neuronal survival and, likely, in

synaptic plasticity and memory formation, anti-Aβ



88

antibodies should be designed to spare Aβ

monomers. At present, whether passive

immunotherapy with bapineuzumab may have

influenced Aβ monomer levels or functions is

unknown. Interestingly, it has been recently

demonstrated that free human Ig γ heavy chains

(HC), which ameliorate Aβ oligomer-induced

impairment of rodent hippocampal LTP, bind

selectively to fibrils and oligomers, but not to

native Aβ monomers /2/. Conformation-specific

antibodies, which bind with high specificity to

ADDLs, are being developed as a new

immunotherapeutic approach to AD and might

become available for clinical trials in the near

future /32/.

The best alternative to anti-Aβ immunotherapy

is believed to be the use of inhibitors of β-secretase

(BACE 1) and -secretase, due to the essential role

of these enzymes in the generation of Aβ from

APP /74/. Whereas only one BACE 1 inhibitor

(CTS-21166) has proceeded to clinical testing /53/,

-secretase inhibitors have failed to show a

significant clinical effect in trials conducted in

patients with mild to moderate AD /17/. Initial

positive results in mild AD were observed with

tarenflurbil, a selective Aβ-lowering agent (SALA)

/80/, but a very recent phase III 18-month,

randomized, placebo-controlled, double-blind trial

study clearly showed a non significant effect of

this drug in outcome measures of cognition /22/.

Overall, the anti-Aβ approaches in clinical

testing have been disappointing. The question now

is to understand why, so that future efforts can be

more successful. Indeed, as opposed to amyloid

plaques, Aβ oligomers were found increased in

some AD patients who received the AN-1792

vaccine /54/, suggesting that the elevated pool of

soluble Aβ oligomers was left unaltered or could

have promoted the progression of the disease. The

alternative explanation is that the vaccination

strategy might have removed the neuroprotective

Aβ monomers, thus exacerbating the course of the

disease. A depletion of Aβ monomers may explain

the lack of efficacy of tested -secretase inhibitors.

Low concentrations of Aβ(1-42) monomers, as

measured by different (enzyme-linked immuno-

absorbent assays) ELISAs, both in the CSF and in

the plasma, predict the conversion of mild

cognitive impairment (MCI) to AD, and parallel

brain Aβ deposition /37,82/. Similarly, low CSF

levels of Aβ(1-40), which is endowed with

neuroprotective activity as Aβ(1-42) /20/, have

been observed in MCI patients with a more rapid

cognitive decline /24/. More recently, low plasma

Aβ(1-42) levels have also been found in depressed

elders with cognitive deficits and no obvious risk

factor for AD (i.e., presence of ApoE4 allele) /70/.

To date, decreased levels of CSF or plasma Aβ(1-

42) monomers are considered a premorbid bio-

marker for AD that merely reflects the increasing

insolubility of Aβ in the brain, and does not

provide causality with AD. Nevertheless, given the

neuroprotective activity of Aβ monomers, we must

consider that a depletion of Aβ monomers in the

preclinical phase of AD might be involved in AD

progression.

Interestingly, reduced CSF Aβ levels are also

seen in neurodegenerative diseases other than AD,

including progressive supranuclear palsy and

corticobasal degeneration /47/ dementia with Lewy

bodies /43/, amyotrophic lateral sclerosis /66/, and

Creutzfeldt-Jacob disease /50/. Thus, decreased Aβ

levels in the CSF may occur without amyloid

deposition in the brain. Although the nature of this

event remains unclear, and probably relays on

disparate mechanisms affecting Aβ metabolism, it

strengthens the idea that Aß may functions as an

endogenous broad-spectrum neurotrophic factor.

A full comprehension of the mechanisms that

regulate A metabolism, together with the

elucidation of the factors that in vivo contribute to

maintain Aβ in an active monomeric conformation,

will be essential for the design a new generation of

therapeutics for AD. Along this line, the study of

metal dyshomeostasis related to A oligomeri-

zation in AD (reviewed in /65/) has led to the

development of metal-protein attenuating

compounds (MPACs) able to inhibit Zn2+

- and

Cu2+

-induced A oligomerizations without

affecting transition-metal homeostasis. PBT2 is the

only MPAC being tested in the clinic.

Interestingly, the results from a phase IIa trial with

PBT2 in 78 patients with early AD indicate a time-

and dose-dependent improvement of executive

functions over placebo in the PBT2 subject group

/34/. Recent findings /4/ indicated that copper and

zinc ionophores are able to induce the degradation

of A by the metal-dependent up-regulation of


VOLUME 21, NO. 1, 2010

89

metalloproteases. It is intriguing that the

expression of metalloproteases by metal-

complexes depends on the activation of the PI-3-K

pathway, the downstream inhibition of the

glycogen synthase kinase 3and the activation of

extracellular regulated kinases /9/, suggesting that

metal-complexes might also have an impact on the

activation of neuroprotective signaling pathways.

The use of aggregation inhibitors can be

viewed as a promising strategy aimed at reducing

the transition of neuroprotective Aβ monomers into

toxic oligomeric species /9/. The notion that early,

soluble Aβ intermediates are key agents in the

cytotoxic effect causing neuronal death suggests

that a major effort should be directed toward the

inhibition of amyloid aggregation at very early

stages. Therefore, agents that target the basic

molecular recognition process preceding the

formation of early intermediates would be the most

valuable candidates. Either natural or synthesized

compounds are being studied, thus providing an

exciting future area for the development of new

therapeutics /3/. Current short peptides or peptide-

mimetics inhibitig A self-association /15/ act by

recognizing A amyloidogenic “hotspots” regions,

a process essentially driven by hydrophobic

interactions, and impeding further growth of the

well-ordered amyloid chain. Yet, peptidic anti-

fibrillogenic agents may be easily inactivated by

proteolysis.

We have conjugated a trehalose moiety to a

peptide inhibitor of A aggregation, the LPFFD,

also referred to as iA5p /68/, thus developing a

new class of protease-resistant inhibitors of A

toxicity /11/. According to the mechanism

proposed by Blackley et al. /5/, trehalose-

conjugated peptides do not necessarily interfere

with the elongation phase of the fibrils, but may act

instead at the level where the globular oligomer

species start to assemble. Interestingly, these novel

glyco-peptide inhibitors recognize and bind the

monomeric form of Athereby delaying and

reducing A aggregation burden (Fig. 2) /11/.

CONCLUSIONS

Originally considered a toxic waste of APP

metabolism, Aß is now revealed as an endogenous

regulator of synaptic activity and a neuroprotective

Fig 2: Schematic representation of the amyloid aggregation steps from monomeric to fibrillar assembly states. Unlike beta-sheet

breakers, glycopeptide inhibitors of Aβ aggregation act in a very early stage of the process as monomer stabilizers, halting

the formation of toxic intermediate species.



90

factor. This knowledge advances our understanding

of the processes leading to the neuropathology of

AD and conceivably will help us to design better

therapeutic strategies.

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The Monomer State of Beta-Amyloid: Where the Alzheimer's Disease Protein Meets Physiology