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R E V I E W
Opportunities and challenges in developing Alzheimer diseasetherapeutics
Khalid Iqbal Inge Grundke-Iqbal
Received: 5 August 2011 / Revised: 17 September 2011/ Accepted: 17 September 2011 / Published online: 30 September 2011
Springer-Verlag 2011
Abstract Alzheimer disease (AD) is a chronic, progres-
sive disorder with an average disease progression of710 years. However, the histopathological hallmark
lesions of this disease, the extracellular Ab plaques and the
intraneuronal neurofibrillary tangles, start as early as
childhood in the affected individuals. AD is multifactorial
and probably involves many different etiopathogenic
mechanisms. Thus, while AD offers a wide window of
opportunity that practically includes the whole life span of
the affected individuals, and numerous therapeutic targets,
the multifactorial nature of this disease also makes the
selection of the therapeutic targets an immensely challeng-
ing task. In addition to b-amyloidosis and neurofibrillary
degeneration, the AD brain also is compromised in its ability
to regenerate by enhancing neurogenesis and neuronal
plasticity. An increasing number of preclinical studies in
transgenic mouse models of AD show that enhancement of
neurogenesis and neuronal plasticity can reverse cognitive
impairment. Development of both drugs that can inhibit
neurodegeneration and drugs that can increase the regen-
erative capacity of the brain by enhancing neurogenesis and
neuronal plasticity are required to control AD.
Keywords Alzheimer disease
Abnormally hyperphosphorylated tau Neurogenesis
Neuronal plasticity
Ciliary neurotrophic factor
Introduction
Alzheimer disease (AD) is the single major cause of
dementia in the middle- to old-aged individuals. Currently,
over 35 million people worldwide are suffering from AD
and this number is projected to triple by 2050 if no drug is
developed that can prevent or inhibit this disease. AD is
multifactorial and probably involves several different et-
iopathogenic mechanisms [42, 43].
The familial form of AD, which accounts for\1% of all
cases, is caused by certain point mutations in b-amyloid
precursor protein, presenilin 1 or presenilin 2 genes [7].
The exact causes of the sporadic form of AD, which
accounts for over 99% of the cases, are not yet understood.
Individuals who inherit one or two APOE4 alleles carry a
*3.5-fold or*10-fold risk, respectively, of coming down
with AD [20].
Histopathologically the familial and the sporadic forms
of AD are indistinguishable from each other and are
characterized by neurodegeneration of the brain, especially
the hippocampus and the rest of the neocortex that is
associated with numerous intraneuronal neurofibrillary
tangles and the extracellular deposits ofb-amyloid as cores
of neuritic (senile) plaques. Although the discoveries of
Ab, which is seen both as plaque core b-amyloid and as
congophilic angiopathy [33, 60] and of abnormal hyper-
phosphorylation of tau as the protein subunit of paired
helical filaments (PHF)/neurofibrillary tangles [35, 44]
were made in around the same period, the immense pop-
ularity of the Amyloid Cascade Hypothesis, according to
which b-amyloid is the primary cause of neurodegenera-
tion and dementia in AD [36, 37] resulted in Ab as the
focus of a large majority of studies on biology and drug
development of AD. However, to date, Ab-based thera-
peutics of AD have been unsuccessful. While on one hand
This article is dedicated to the celebration of Prof. Kurt Jellingers
80th birthday, which was on May 28th.
K. Iqbal (&) I. Grundke-Iqbal
Department of Neurochemistry, New York State Institute
for Basic Research in Developmental Disabilities,
1050 Forest Hill Road, Staten Island, NY 10314-6399, USA
e-mail: [email protected]
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it is truly a great setback in the development of disease-
modifying drugs, it has increased awareness of the
involvement of several different etiopathogenic mecha-
nisms and stimulated research on non-Ab-based therapeutic
approaches to this disease.
Opportunities
AD is a chronic, progressive, neurodegenerative disease
with an average progression of 710 years. However, the
histopathological hallmarks of this disease, the neurofi-
brillary tangles of abnormally hyperphosphorylated tau and
Ab plaques, are known to occur many years before the
clinical expression of the disease [12]. A recent study by
Braak and Tredici [13] have shown that neurofibrillary
degeneration of abnormally hyperphosphorylated tau
occurs as early as in early childhood and starts from select
subcortical nuclei. Neurodegeneration of the AD type
probably occurs throughout the life of an individual andclinically manifests when it crosses a certain threshold. In
the familial form of AD, which is caused by certain
mutations, this process is mostly more accelerated than in
the sporadic form and, thus, results in dementia at an earlier
age. In the case of Down syndrome, a developmental dis-
ease with severe mental retardation, which is caused by an
extra copy of chromosome 21, in the fourth decade of life
without fail these affected individuals develop AD histo-
pathology, i.e. numerous plaques and tangles in the
forebrain. It is possible that, like Down syndrome, AD is a
developmental disorder, the clinical phenotype of which
does not become apparent until middle- to old-age. Thus,
AD offers for therapeutic treatment a window of opportu-
nity that extends practically the whole life span of the
affected individuals.
There are at least five subgroups of sporadic AD. These
subgroups, each of which displays different clinical pro-
files, were identified based on the CSF levels of Ab142,
total tau, and ubiquitin [42]. Though AD is histopatho-
logically characterized by the presence of numerous Ab
plaques and neurofibrillary tangles of abnormally hyper-
phosphorylated tau, each of these lesions can result from
different etiological factors and upstream molecular
mechanisms. For instance, dysregulation of a-, b-, or c-
secretase activity can all lead to b-amyloidosis [19, 65, 67].
The abnormal hyperphosphorylation of tau that leads to its
aggregation into paired helical filaments that form neuro-
fibrillary tangles and neuropil threads can be generated by
several different combinations of proline-directed protein
kinases (PDPKs) and non-PDPKS [89]. These reports are
consistent with the involvement of several different etio-
pathogenic mechanisms of AD. Thus, AD offers a large
number of therapeutic targets.
Challenges
To date therapeutic attempts, which included inhibition
of Ab production, its aggregation as well as removal
from the brain, have all been unsuccessful. Based on
what is known about AD and Ab to date, there could be
four major reasons for the failure of the Ab-based
therapeutics:First, b-amyloid could be a non-deleterious marker and
not a cause of the disease. It is well established that as
many as 30% of the normal elderly have as much b-amy-
loid plaque load as typical cases of AD, and the number of
plaques in AD does not correlate with the degree of
dementia [5, 21, 50, 75]. Only some of the presenilin-1 and
presenilin-2 mutations that produce AD result in increased
brain levels of Ab; some of the AD-causing mutations
either result in no change or a decrease in brain Ab levels
[69, 73]. While in cultured cells and in experimental ani-
mals Ab has been found to be neurotoxic, these findings
were made with either treatment or overexpression with avery high non-physiological concentration of Ab. Although
a lot has been learned about Ab during the last*25 years,
there is still not any conclusive evidence and, thus,
agreement on what form, state, cellular/extra cellular
location, if and how Ab causes AD.
Another possibility is that inhibition or removal of Ab
alone is not enough to inhibit AD. Both in cultured cells
and in vivo in transgenic mice studies have shown that Ab
neurotoxicity requires tau [72, 74]. Thus, Ab-based therapy
with a concomitant tau-based therapy might be required for
successful treatment of AD.
Second, the Ab-based therapeutics employed so far were
not potent enough to ameliorate the disease. In the case of
Flurizan (Myriad Genetics, USA), a c-secretase inhibitor,
the drug had no serious side effects but failed in Phase III
clinical trials. Samagucestat (Eli Lilly & Company, USA),
a potent c-secretase inhibitor, made AD patients worse as
well as increased the risk for skin cancer, probably due to
non-selectivity of this drug to c-secretase activities towards
other substrate proteins; there are about 50 other proteins
including NOTCH which are c-secretase substrates. Al-
zhamed (Neurochem, Inc., Canada), an Ab aggregation
inhibitor, Tramiprosate, had no serious side effects and
failed in Phase III clinical trials. Ab vaccine (Elan Cor-
poration, Ireland) successfully removed Ab plaques from
brain parenchyma but increased congophilic angiopathy
and in around 5% of the subjects caused meningoenceph-
alitis and the Phase III clinical trial had to be halted.
However, the treated patients failed to show any inhibition
of cognitive deterioration. Development of an Ab vaccine
that does not produce congophilic angiopathy and menin-
goencephalitis is eagerly awaited. Unlike active, the
passive immunization using a monoclonal antibody to Ab,
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Bapineuzumab, failed to show any clinical improvement in
a large Phase II clinical trial carried out by Elan Corp.
Third, all Ab-based therapies were tested in mild to
moderate cases of AD which was too late to see any
inhibition of cognitive decline. AD is a chronic, progres-
sive, neurodegenerative disease where the pathology starts
decades before the onset of any clinically detectable signs.
Principally, the earlier the better and the easier it is to treata disease. However, given the fact that AD is a chronic,
progressive, neurodegenerative disease where the pathol-
ogy starts several decades before the clinical onset of the
disease, it is unlikely that the Ab drugs were unsuccessful
because clinically diagnosed mild to moderate and not
predromal state patients were treated.
Fourth, the Ab-based drugs might be effective only
towards a small subgroup of this multifactorial disease.
There are at least five subgroups of AD and in one of these
five subgroups, called HARO, the CSF Ab levels are ele-
vated whereas in the remaining four subgroups, AELO,
ATEO, LEBALO and ATURO, it is the opposite [42]. IfAb-based therapies are effective only towards a specific
small subgroup of AD, it will be difficult to see any posi-
tive outcome without stratifying patients into various
subgroups.
The multifactorial nature and the likely involvement of
several different etiopathogenic mechanisms pose the most
difficult challenge for the development of AD therapeutics.
To develop rational therapeutic strategies and drugs, bio-
markers and procedures to identify various subgroups as
well as determination of the etiopathogenesis of each
subgroup are required (Fig. 1).
Neuroregeneration, a therapeutic strategy
Independent of the various etiopathogenic mechanisms
involved in AD, they all cause neurodegeneration. Thus, a
successful therapeutic strategy for AD may include both
inhibition of neurodegeneration as well as stimulation of
regeneration of the affected areas of the brain. The latter
can be achieved by drugs that can promote both neuro-genesis and neuronal plasticity.
Several lines of evidence are consistent with the
involvement of neurogenesis in memory in the adult brain.
In particular, adult-born hippocampal neurons have been
implicated in complex forms of spatial or associative
memories [2, 3, 53, 57]. Dysregulation of neurotrophic
activities, either due to age, genetic background or other
unknown factors, has been implicated in neurodegeneration
and mood disorders [38]. There is an imbalance between
neurogenesis and neurodegeneration in AD and other
neurodegenerative disorders [30, 41, 68]. Several studies
have suggested that age-associated decline in neurogenesismight contribute to a pathological condition and the asso-
ciated learning and memory decline in AD [46, 55] and in
transgenic mouse models of this disease [26, 28, 39, 40,
88]. The neurogenic decline and associated cognitive
impairment happen prior to the formation of any Ab pla-
ques or neurofibrillary tangles in 3xTg-AD mice,
suggesting that the down regulation of neurogenesis could
be a component of the primary pathology caused by the
expressions of mutated human APP, presenilin 1 and tau in
these animals [9]. Neuronal survival during maturation is
believed to depend on the surrounding microenvironment.
Fig. 1 Multifactorial nature of
Alzheimer disease and
involvement of several different
disease mechanisms. APP,
b-amyloid precursor protein;
PS1, presenilin 1; PS2,
presenilin 2; Inflam,
inflammation; SETa, inhibitor-2
of protein phosphatase 2A;
TBD, to be determined
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The microenvironment of the dentate gyrus (DG) in neu-
rodegenerative conditions apparently becomes adverse for
maintaining greater levels of neurogenesis [34, 87]. In AD,
the DG neuroproliferation is increased [45] but the newly
generated neurons apparently do not mature [55].
Both newly born immature and mature neurons are
believed to have an inherent advantage to be recruited into
patterns of new memory networks [48] and are necessary for
complex forms of hippocampal-mediated learning [3, 29].
The hippocampus is particularly vulnerable to neurodegen-
eration and hippocampal-dependent memory impairment isreported as the earliest symptom of dementia [6]. Thus, con-
sidering the regenerative ability of the brain, treatments
promoting neuronal differentiation enriching the biochemical
brain milieu could be a successful therapy for AD and related
neurodegenerative disorders [8, 9, 18, 49, 54, 88].
In AD, the most significant correlate to the severity of cog-
nitive impairment is the synaptic loss in the frontal cortex and
the limbic system [24, 25, 59, 82]. In the mature brain, neuro-
genesis is believed to play an important role in maintaining
synaptic plasticity and memory formation in the hippocampus
[86]. Both AD as well as transgenic mouse models of AD show
significant alterations in the process of neurogenesis in thehippocampus [17, 2628, 45, 88, 90]. Thus, alterations in syn-
aptic plasticity in AD might not only involve direct damage to
the synapses, but also interference with neurogenesis.
Neurogenesis in the aging brain can be promoted by
increasing the level of pro-neurogenic factors like neuros-
teroids [47, 61], cell-cycle regulators [62], NMDA receptor
antagonists [63], and growth factors [1, 4, 46, 71, 83].
Neurotrophins and neurokines have been shown to be
involved in the promotion of survival of subsets of neurons
vulnerable in neurodegenerative diseases [23, 76, 78, 85].
Several different approaches have been employed to enhance
neurogenesis and/or neuronal plasticity to improve cognition
in different animal models of AD. These strategies included
direct implantation of neural stem cells in the brain of 3xTg-
AD mice [10]; stimulation of hematopoietic stem cell pro-
duction by subcutaneous administration of granulocyte
colony stimulating factor in Tg2576 and Tg-APP/PS1 mice
[77, 84]; intraperitoneal administration of macrophage colony
stimulating factor in Tg-APP/PS1 mice [11]; delivery of
CNTF by implantation of recombinant cells secreting theneurotrophic factor encapsulated in alginate polymers [32];
and the entorhinal administration of the brain-derived neuro-
trophic factor in several animal models of AD [64]; the
neuroprotective effect observed in this latter study was
through amyloid-independent mechanisms (Fig. 2).
Growth factors such as insulin-like growth factor (IGF-1)
[56], epidermal growth factor (EGF), and fibroblast growth
factor (FGF-2) [46] or a reduction of corticosteroids level by
adrenalectomy [14] can at least partially negate the effect of
age on the rate of neural stem proliferation. This environment-
dependent positive regulation of neurogenesis supports the
idea that the age-associated loss of new neurons is not anirreversible mechanism which, if triggered by appropriate
signals, can be reactivated in the senescent brain.
Enhancement of neurogenesis and neuronal plasticity
with ciliary neurotrophic factor peptidergic drugs
Ciliary neurotrophic factor (CNTF) promotes neurogenesis
both in hippocampus and subventricular zone [31, 91]. In
Fig. 2 Pathogenesis of
Alzheimer disease and the two
major therapeutic strategies
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the brain CNTF is expressed in subsets of astrocytes in the
neurogenic regions, whereas its receptor, CNTFRa, seems
to be expressed mostly in progenitor cells and neurons of
the hippocampus and various other areas of the brain,
including motorcortex and cerebellum [31, 52, 80]. CNTF
belongs to the IL-6 family of cytokines which also includes
IL-11, leukemia inhibitor factor (LIF), oncostatin-M, car-
diotrophin-1, and cardiotrophin-like cytokine [79, 81].CNTF signaling occurs through the formation of a tripartite
complex of CNTFRa, the LIFb receptor (LIFR) and gly-
coprotein 130 (gp130). CNTF and LIF both signal through
tyrosine phosphorylation of the signal transducers and
activators of transcription (STAT) proteins by the mem-
brane-associated Janus kinase (JAK) [22]. Upon injury of
the brain, the expression of both CNTF and CNTFRa
increases [51, 52, 58].
Like other neurotrophins [70], the therapeutic potential
of exogenous CNTF is eclipsed by its short half-life when
administered peripherally, requiring an invasive mode of
administration with unpredictable pharmacokinetics [16].Moreover, the clinical use of CNTF, due to its serious side
effects, i.e. anorexia, skeletal muscle loss, hyperalgesia,
cramps and muscle pain, has not materialized.
In our laboratory, employing neutralizing antibodies to
CNTF, we identified the amino acid residues 146156 as an
active region of this neurotrophic factor [15, 18]. Periph-
eral administration of this 11-mer CNTF peptide, named
Peptide 6, for 30 days enhanced dentate gyrus neurogene-
sis and neuronal plasticity in normal adult C57BL6 mice
[18]. This peptide, Peptide 6, induced proliferation and
increased survival and maturation of neural progenitor cells
into neurons in the dentate gyrus. Furthermore, Peptide 6
increased the MAP2 and synaptophysin immunoreactivity
in the dentate gyrus. The 30-day treatment with a slow
release bolus of the peptide implanted subcutaneously
improved reference memory of the mice in the Morris
water maze. Peptide 6 had a plasma half-life of over 6 h,
was bloodbrain barrier permeable, and acted by compet-
itively inhibiting the LIF signaling.
Like AD, several transgenic mouse models of this dis-
ease show failed hippocampal neurogenesis and cognitive
impairment. The triple transgenic AD (3xTg0-AD) mouse
represents one of the most biologically relevant animal
models of AD described so far [66]. The 3xTg-AD mice
harbor three AD-related genetic loci: human PS1M146V,
human APPSWE, and human tauP301L. These mice develop
b-amyloid plaques and neurofibrillary tangle-like patholo-
gies in a progressive and age-dependent manner, starting at
around 12 months but show cognitive impairment as early
as around 5 months. Treatment of 6- to 7-month-old 3xTg-
AD mice with intraperitoneal administration of Peptide 6
for 6 weeks restored cognition by enhancing dentate gyrus
neurogenesis and neuronal plasticity in these animals [9].
Interestingly, the treatment with Peptide 6 had no detect-
able effect on Ab and tau pathologies, which at this age in
these mice is seen as intraneuronal accumulation of Ab and
tau and not as plaques and tangles.
In subsequent studies we narrowed down the minimal
active region of Peptide 6 to 4 amino acids, D G G L [8]. The
neurogenic and neurotrophic activities of this tetrapeptide,
Peptide 6c, are preserved when it is carboxy adamantylatedto enhance its lipophilicity [54]. Thus, preclinical studies
clearly suggest enhancement of neurogenesis and neuronal
plasticity as a promising approach to restore cognition in AD
and related neurodegenerative cognitive disorders.
Acknowledgments We are grateful to Janet Murphy for secretarial
assistance. Studies from our lab described in this article were sup-
ported in part by NIH grants AG019158, AG028538, Alzheimers
Association grant IIRG-06-25836, a research grant from EVER
Neuropharma, Unteract, Austria, and by the New York State Office of
People with Developmental Disabilities.
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