Acta Neuropathol (2011) 122:543549 DOI 10.

1007/s00401-011-0878-z

REVIEW

Opportunities and challenges in developing Alzheimer disease therapeutics

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, progressive disorder with an average disease progression of 710 years. However, the histopathological hallmark lesions of this disease, the extracellular Ab plaques and the intraneuronal neurobrillary 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 challenging task. In addition to b-amyloidosis and neurobrillary 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 regenerative 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 etiopathogenic 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 neurobrillary tangles and the extracellular deposits of b-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 hyperphosphorylation of tau as the protein subunit of paired helical laments (PHF)/neurobrillary tangles [35, 44] were made in around the same period, the immense popularity of the Amyloid Cascade Hypothesis, according to which b-amyloid is the primary cause of neurodegeneration 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 therapeutics 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: khalid.iqbal.ibr@gmail.com

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it is truly a great setback in the development of diseasemodifying drugs, it has increased awareness of the involvement of several different etiopathogenic mechanisms and stimulated research on non-Ab-based therapeutic approaches to this disease.

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-amyloid 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 animals Ab has been found to be neurotoxic, these ndings were made with either treatment or overexpression with a very 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. Alzhamed (Neurochem, Inc., Canada), an Ab aggregation inhibitor, Tramiprosate, had no serious side effects and failed in Phase III clinical trials. Ab vaccine (Elan Corporation, Ireland) successfully removed Ab plaques from brain parenchyma but increased congophilic angiopathy and in around 5% of the subjects caused meningoencephalitis 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 meningoencephalitis is eagerly awaited. Unlike active, the passive immunization using a monoclonal antibody to Ab,

Opportunities AD is a chronic, progressive, neurodegenerative disease with an average progression of 710 years. However, the histopathological hallmarks of this disease, the neurobrillary 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 neurobrillary 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 and clinically 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 disease 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 histopathology, 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 opportunity that extends practically the whole life span of the affected individuals. There are at least ve subgroups of sporadic AD. These subgroups, each of which displays different clinical proles, were identied based on the CSF levels of Ab142, total tau, and ubiquitin [42]. Though AD is histopathologically characterized by the presence of numerous Ab plaques and neurobrillary tangles of abnormally hyperphosphorylated tau, each of these lesions can result from different etiological factors and upstream molecular mechanisms. For instance, dysregulation of a-, b-, or csecretase activity can all lead to b-amyloidosis [19, 65, 67]. The abnormal hyperphosphorylation of tau that leads to its aggregation into paired helical laments that form neurobrillary 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 etiopathogenic mechanisms of AD. Thus, AD offers a large number of therapeutic targets.

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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, progressive, 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 treat a disease. However, given the fact that AD is a chronic, progressive, neurodegenerative disease where the pathology 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 ve subgroups of AD and in one of these ve subgroups, called HARO, the CSF Ab levels are elevated whereas in the remaining four subgroups, AELO, ATEO, LEBALO and ATURO, it is the opposite [42]. If Ab-based therapies are effective only towards a specic small subgroup of AD, it will be difcult to see any positive outcome without stratifying patients into various subgroups. The multifactorial nature and the likely involvement of several different etiopathogenic mechanisms pose the most difcult challenge for the development of AD therapeutics. To develop rational therapeutic strategies and drugs, biomarkers and procedures to identify various subgroups as well as determination of the etiopathogenesis of each subgroup are required (Fig. 1).
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; Inam, inammation; SETa, inhibitor-2 of protein phosphatase 2A; TBD, to be determined

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 neurogenesis 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 neurogenesis might contribute to a pathological condition and the associated 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 plaques or neurobrillary 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.

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546 Fig. 2 Pathogenesis of Alzheimer disease and the two major therapeutic strategies

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The microenvironment of the dentate gyrus (DG) in neurodegenerative 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 neurodegeneration and hippocampal-dependent memory impairment is reported as the earliest symptom of dementia [6]. Thus, considering 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 signicant correlate to the severity of cognitive impairment is the synaptic loss in the frontal cortex and the limbic system [24, 25, 59, 82]. In the mature brain, neurogenesis 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 signicant alterations in the process of neurogenesis in the hippocampus [17, 2628, 45, 88, 90]. Thus, alterations in synaptic 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 neurosteroids [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 3xTgAD mice [10]; stimulation of hematopoietic stem cell production 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 the neurotrophic factor encapsulated in alginate polymers [32]; and the entorhinal administration of the brain-derived neurotrophic 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 broblast 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 environmentdependent positive regulation of neurogenesis supports the idea that the age-associated loss of new neurons is not an irreversible 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

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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, cardiotrophin-1, and cardiotrophin-like cytokine [79, 81]. CNTF signaling occurs through the formation of a tripartite complex of CNTFRa, the LIFb receptor (LIFR) and glycoprotein 130 (gp130). CNTF and LIF both signal through tyrosine phosphorylation of the signal transducers and activators of transcription (STAT) proteins by the membrane-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 identied the amino acid residues 146156 as an active region of this neurotrophic factor [15, 18]. Peripheral administration of this 11-mer CNTF peptide, named Peptide 6, for 30 days enhanced dentate gyrus neurogenesis 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 competitively inhibiting the LIF signaling. Like AD, several transgenic mouse models of this disease 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 neurobrillary tangle-like pathologies 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 3xTgAD 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 detectable 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 adamantylated to 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 supported 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 Ofce of People with Developmental Disabilities.

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