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Neuroprotective peptides as drug candidates against Alzheimer's disease

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 J. Appl. Biomed.
3:67–73, 2005
ISSN 1214-0287

REVIEW

Neuroprotective peptides as drug candidates against Alzheimer’s

diasease

Jiří Patočka1,2, Jiřina Slaninová3, Gabriela Kunešová1

1
Department of Toxicology, School of Military Health Sciences, University of Defence, Hradec Králové, Czech
Republic
2
Department of Radiobiology and Toxicology, Faculty of Health and Social Studies, University of South
Bohemia, České Budějovice, Czech Republic
3
Institute of Organic Chemistry and Biochemistry, Academy of Sciences, Praha, Czech Republic

Received 5th November 2004.

Revised 6th December 2004.
Published online 16th March 2005.

Summary
First described by Alois Alzheimer in 1907, Alzheimer's disease (AD) is the most common dementia
type, affecting approximately 20 million people worldwide. As the population is getting older, AD is a
growing health problem. AD is characterized by the presence of neuritic plaques containing the amyloid-
beta peptide (Abeta) and an intraneuronal accumulation of tubule-associated protein called tau. Currently
available treatment used in AD is based on acetylcholinesterase inhibitors, since in the course of AD
there is a substantial loss in cholinergic neurons. Another registered drug used in more severe AD is the
NMDA antagonist-memantine. From a drug development point of view, some potential new AD
therapeutics include neuroprotective peptides that may act in a variety of different ways, e.g. they help to
break the amyloid plaque formation, modulate peptide processing enzymes (secretases) or are able to
degrade Abeta toxic peptide. In this review, we present an overview of the new classes of compounds in
use against AD.

Keywords: Alzheimer's disease – neuroprotective peptide – Abeta peptide

INTRODUCTION characterised by progressive dementia and the

decline of intellectual functions. It is the most
Alzheimer’s disease (AD) and related common cause of dementia among people aged
neurodegenerative disorders represent serious 65 and older. A contemporary estimate of sufferers
neurodegenerative disorders, are prevalent among is approximately 20 million AD patients
worldwide. In fact, nearly 30% of all people aged
85 and older are thought to have AD. It has been
Jiří Patočka, Department of Toxicology, predicted that with our ageing population, by the
School of Military Health Sciences, Trebešská year 2050 the AD patient population will almost
1575, University of Defence, 50001 Hradec double to become over 14 million people in the
Králové, Czech Republic. United States alone. It is thus of high importance to
[email protected] develop therapies to combat the disease and
alleviate the devastating outcome. The drugs
 J. Patočka et al.: Neuroprotective peptides against Alzheimer’s diasease

currently available treat mainly the decline in brain identity of γ-secretase, which is responsible for the
acetylcholine concentration, by means of inhibiting intramembranous processing of APP, is still
the acetylcholinesterase pathway leading to enigmatic, although it was suggested that the
acetylcholine breakdown. However, in the best membrane spanning presenilins (PS1 and PS2)
case this apparently contributes to improving the function as γ-secretases (Sisodia et al. 2001).
disease symptomatology for only a limited time Though AD is largely a sporadic disease, mutations
period. It targets the cholinergic neurons – the most in APP and presenilins as well as the lipid carrier
vulnerable population of neurons in the first stages apolipoprotein E4 allele have been associated with
of AD. hereditary AD (Sisioda and Tanzi 2001).
Four drugs, which all act in the same way to AD is characterized by overproduction of
increase levels of acetylcholine, are currently used Abeta in the brain and with progressive loss of
to improve symptomatic cognitive function in neuronal cells. The 42-amino acid form of the
patients diagnosed with AD, i.e. Cognex (tacrine), Abeta (Abeta42) is implied as a major causative
Aricept (donepezil), Exelon (rivastigmine), and factor, because it causes neuronal death through
Reminyl (galantamine). They have not been shown, apoptosis and elicits inflammatory responses in the
however, to alter the long-term progression of the brain by activating microglial cells. Intracellular
disease. The majority of newly developing Abeta42 accumulates in the AD patients brain
antidementia drugs are also cholinesterase before plaque and tangle formation (Gouras et
inhibitors. Only some of them are based on other al. 2000) and is extremely toxic to human neuronal
mechanisms of action, for example inhibitors of the cells in vitro (Zhang et al. 2002).
NMDA ionotropic neurotransmitter receptors, such In addition to the Abeta plaques, the
as memantine (Patočka 2001), although neurofibrillary tangles composed of
galantamine could act as a nicotinic receptor hyperphosphorylated microtubule-associated
allosteric ligand potentiating the effect of protein tau form inside the cells. Recent studies
acetylcholine at receptor level. From a drug suggested that Abeta exposure may result in rapid
development point of view, some potential new tyrosine phosphorylation of neuronal proteins
Alzheimer’s disease therapeutics include peptides including tau and enhanced formation of
that may act in a variety of different ways, e.g. neurofibrillary tangles (Gotz et al. 2001,
help to break the amyloid plaque formation, Williamson et al. 2002). Glycogen synthase kinase
modulate peptide processing enzymes (secretases) 3 (GSK-3), a serine/threonine protein kinase that
or are able to degrade Abeta toxic peptides. In such has been shown to be increased in AD, leads to tau
a context, current research projects are specifically hyperphophorylation and apoptosis (Eldar-
focused on reducing the formation of brain lesions Finkelman 2002) and some GSK-3 inhibitors, such
resulting from the disease, especially those due to as lithium, can served in the prevention of
the amyloid peptide accumulation, and on reducing Alzheimer's disease (Strunecká and Patočka 2004).
or even halting the clinical evolution of the disease
and consequent neurodegenerative processes
(Nieoullon 2004).
Peptides provide an attractive alternative but NEUROPROTECTIVE PEPTIDES IN AD
there are still some unanswered questions (Gozes
2001). For example, it is not quite clear if peptides Despite the overproduction of Abeta42, AD brain
are able to cross the blood-brain barrier. tissue also generates protective factor(s) that may
Nevertheless, peptides are important candidates for antagonize the neurodestructive effect of Abeta.
future drug development (Gozes and Spier 2002). New pieces of evidence show that AD is associated
with changes in the gene expression of many
neuropeptides in the brain and their content in the
cerebrospinal fluid (CSF). The significance of these
NEUROTOXIC PEPTIDES IN AD changes resides in the fact that these neuropeptides
may convey neuroprotection or induce changes in
The pathogenesis of AD is most probably neuronal viability (Slaninová and Patočka 2003). In
connected with the deposition of beta-amyloid addition to the natural peptides, several of their
(Abeta) peptides in the cerebral cortex and synthetic analogues and fragments were studied for
hippocampus of affected individuals. Abeta neuroprotectivity.
peptides (the family of 40–43 amino acid long The neuroprotective potential of different
peptides) are derived from transmembrane protein, peptides has become a matter of intensive
termed amyloid precursor protein (APP), by investigation in many animal models. Many in vitro
concerted action of the enzymes termed β- and studies reveal that peptides protect neurons against
γ-secretase(s). In contrast, α-secretase cleaves APP apoptosis occurring naturally during CNS
at a position that leads to nontoxic peptides. development and apoptosis induced by a series of
Recently, β-secretase was identified. However, the neurotoxins, prion protein, Abeta, HIV envelope

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 J. Patočka et al.: Neuroprotective peptides against Alzheimer’s diasease

glycoprotein (gp120), potassium ion deficit, and neuroprotectants and may serve as a goal of
high glutamate concentrations (Sokolowska et al modern therapeutic strategies in various
2004). The neuroprotective potential of peptides neurodegenerative disorders. Minor and less
has not been as thoroughly investigated in all explored peptides of this view are only briefly
peptides yet, but recent data have confirmed that characterized in Table 1.
numerous peptides are able to function as

Table 1. Brief characterization of some neuroprotective peptides

Peptide Neuroprotective and other effects Literature

Somatostatin Somatostatin levels in CSF are consistently decreased in Craft et al. 1999
AD. Somatostatin analogue infusion improved memory for
patients with AD, perhaps through modulation of the
insulin content
Neuropeptide Y (NPY) NPY levels are decreased in AD. It may be involved in Croom and Tailor 2001
aluminium metabolism in animal models, and aluminium Strunecká and Patočka
accumulation has been associated as a risk factor for AD, 2003
mainly in combination with fluorine. Strunecká et al. 2004
Galanin Galanin levels increase with the duration of AD. Galanin Counts et al. 2001,2004
inhibits cholinergic transmission and long term Jhamands et al. 2002
potentiation in hippocampus. Galanin’s excitatory action
on cholinergic neurons may play a compensatory role by
augmenting the release of acetylcholine from remaining
cholinergic basal forebrain neurons.
Insulin like growth factor I IGF I protects in vitro primary neurons from cytotoxic Niikura et al. 2004
(IGF I) mechanism of the London type Abeta PP mutant.
Interleukin-6 and Both interleukins attenuate cytotoxicity of the London type Niikura et al. 2004
Interleukin-11 Abeta PP mutant.
Apoptosis-antagonizing AATF protects neurons against Abeta-induced apoptosis in Xie and Guo 2004
transcription factor (AATF) PC 12 cells
SAL (SALLRSIPA) SAL is active fragment of ADNF and prevents neuronal Brenneman et al. 2004
cell death produced by electrical blockade, N-methyl-D-
aspartate, and Abeta
Activity ADNP is glial cell mediator of VIP associated Bassan et al. 1999
-dependent neuroprotective neuroprotection. The protein implicated in maintenance of Zamostiano et al. 2001
protein (ADNP) cell survival through modulation of p53 expression. The Sigalov et al. 2000
ADNP was identified as a molecule that may mediate
protection offered by lipophilic VIP analogues against
ischemia cell death.
Bcl-w Bcl-w is a member of the Bcl-2 anti-apoptic protein family Zhu et al. 2004
that promotes cell survival, significantly protects neurons Weinreb et al. 2004
against stauroporine and Abeta induced apoptosis.
Gly-Pro-Arg This tripeptide effectively protects and rescues cell death Ioudina and Uemura 2003
induced by Abeta.
RER peptides Peptides containing the palindromic tripeptide RER Mileusnic et al. 2004
sequence (Arg-Glu-Arg), present in the amyloid precursor
protein, protects against memory loss cause by Abeta and
acts as a cognitive enhancer.
Autocamtide-related These peptides inhibit Ca/Calmodulin dependent protein Lin et al. 2004
inhibitory peptides (AIP) kinase II, inhibit Abeta triggered activation of caspase 2
and 3, decrease tau phosphorylation and protect neuron
against Abeta toxicity.
Substance P This short peptide interacts with cholinergic ascending Pompei et al. 2001
system of the nucleus basalis Meynert, resulting Patočka 2002
enhancement effects. Patients with AD show a marked loss
of cholinergic neurons and diminished brain substance P
expression.

69
 J. Patočka et al.: Neuroprotective peptides against Alzheimer’s diasease

VIP (vasoactive intestial peptide), originally developing mouse brain against excitotoxicity
discovered in the intestine, was later found to be a (Gressens et al. 1999).
major brain peptide having neuroprotective NAP (NAPVSIPQ), an eight-amino-acid
activities (Gozes and Brenneman1989). peptide, the smallest active element of ADHP,
Some lipophilic derivatives of VIP cross the provides neuroprotection at very low doses in a
blood brain barrier and provide nerve-cell variety of animal models (Alcalay et al. 2004). It
protection and accelerate learning and memory in was identified as a most potent neuroprotective
animal models (Gozes et al. 1999, Sokolowska et peptide in an animal model of apolipoprotein E
al. 2004). Also PACAP (pituitary adenylate deficiency (knockout mice) (Bassan et al., 1999)
cyclase-activating polypeptide), PHI (peptide and in an animal model of cholinotoxicity (Gozes
histidine-isoleucine), PHM (peptide histidine- et al. 2000). Because apolipoprotein E has been
methionine), and PHV (peptide histidine-valine) implicated as a risk factor in AD, this peptide holds
belong to the same superfamily of peptides as VIP, promise for future treatment against AD-associated
share a high level of structural and functional short-term memory deficits (Gozes et al. 2004). AD
similarity, and have been shown to be is associated with the death of cholinergic neurons
neuroprotective (Dejda et al. 2004). and rats treated with the cholinotoxin ethylcholine
ADNF (activity-dependent neurotrophic factor) aziridium (AF64A) provide a model of
is a recently isolated factor secreted by glial cells cholinotoxicity (Fisher and Hanin 1986). In this
under the action of VIP (Brenneman and Gozes model a significant improvement in short-term
1996). This protein was named ‚activity-dependent spatial memory in NAP-treated animals was
neurotrophic factor‘ as it protected neurons from observed (Gozes et al. 2000). Cognition
death associated with blockade of electrical enhancement was also found in the Morris water
activity. Subsequent structure-activity studies maze in rats treated daily with NAP (Gozes et al.
identified the novel ADNF peptide, ADNF-9, more 2002). NAP-treated animals also exhibit faster
potent than the parent protein and with a broader recovery of motor ability, balancing, and alertness
range of effective concentration (Brenneman et and a single NAP subcutaneous injection after
al.1998). ADNF-9 exhibits protective activity in closed head injury dramatically reduced mortality
Abeta toxicity (Brenneman et al. 1998), presenilin and facilitated clinical recovery in mice
1 mutation (Guo et al. 1999), and apolipoprotein E (Beni-Adani et al. 2000).
deficiencies (Bassan et al. 1999). ADNF-9 provides Humanin is a 24-amino acid peptide, which
protection against oxidative stress (Steingart et al. protects neuronal cells from damage by Abeta42
2000) through maintenance of mitochondrial (Hashimoto et al. 2001; Patočka et al. 2003) and is
function and a reduction in the accumulation of a new peptide in the etiology of Alzheimer's
intracellular reactive oxygen species (Glazner et disease (Patočka and Slaninová 2004). Humanin
al. 1999). ADNF-9 regulates transcriptional induced chemotaxis of mononuclear phagocytes by
activation associated with neuroprotection and using a human G protein-coupled formylpeptide
increases heat shock protein 60 expression, thus receptor-like-1 (FPRL1) and its murine counterpart
providing cellular protection against Abeta toxicity FPR2. Coincidentally, FPRL1 and FPR2 are also
(Zamostiano et al. 1999). functional receptors used by Abeta42 to
In synaptosomes, ADNF-9 enhanced basal chemoattract and activate phagocytic cells.
glucose and glutamate transport, and it attenuates Humanin reduced the aggregation and fibrillary
oxidative impairment of glucose and glutamate formation by suppressing the effect of Abeta42 on
transport induced by Abeta (Guo and Mattson mononuclear phagocytes. In neuroblast cells,
2000) and in hippocampal neurons, ADNF-9 humanin and Abeta42 both activated FPRL1;
stimulated synapse formation (Blondel et al. 2000). however, only Abeta42 caused apoptotic death of
In hippocampal culture system, ADNF-9 caused the cells, and its cytopathic effect was blocked by
the secretion of neurotrophin 3 (NT-3), and both humanin. It was concluded that humanin shares
NT-3 and ADNF-9 regulated NMDA the receptor human FPRL1 and mouse FPR2 with Abeta42 and
subunit 2A (NR2A) and NR2B, suggesting in vivo suggested that humanin may exert its
effects on learning and behavior in the adult neuroprotective effects by competitively inhibiting
nervous system. In a rat model of choline the access of FPRL1 to Abeta42 (Ying et al. 2004).
deficiency, ADNF-9 enhanced performance in a Also some peptides derived from humanin have a
water maze, indicative of spatial learning and neuroprotective effect and represent a beneficial
memory (Gozes et al. 2000). Longer peptides drug for the impairment of learning and memory
including the ADNF-9 sequence, such as (Mamiya and Ukai 2001, Krejčová et al. 2004).
ADNF-14, have been shown to promote axonal Beta sheet breaker peptides represent an
elongation through transcriptionally regulated interesting group of new compounds that are able
cAMP-dependent mechanisms (White et al., 2000) to reverse the effects of pathogenic prion proteins
and to activate protein kinase C and mitogen- (Reily 2000). Since fibril formation Abeta,
associated protein kinase kinase, protecting the considered to be responsible for the pathology of

70
 J. Patočka et al.: Neuroprotective peptides against Alzheimer’s diasease

AD, is formed by a protein misfolding process in ACKNOWLEDGEMENT

which intermolecular beta-sheet interactions
become stabilized abnormally, compounds which The work was supported by the Grant Agency of
have a profile as a beta-sheet breaker can probably Czech Republic No. 305/03/1100. Preparation of
be important as an anti-AD candidate. These the manuscript was supported by Academia Medica
peptides are able to bind soluble amyloid peptide Pragensis Fellowship, Czech Republic.
and prevent and reverse its conversion to the beta-
sheet rich aggregated structure, precursor of the
amyloid plaques (Chacon et al. 2004). Results in
vitro, in cell culture and in vivo suggest that beta-
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