opportunities and challenges 2011

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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]

123

Acta Neuropathol (2011) 122:543549

DOI 10.1007/s00401-011-0878-z


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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,

544 Acta Neuropathol (2011) 122:543549

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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

Acta Neuropathol (2011) 122:543549 545

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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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