Neuroprotection in Alzheimer's Disease

Neuroprotection in Alzheimer's Disease

Edited by

Illana Gozes

Sackler School of Medicine

Tel Aviv University

Tel Aviv, Israel

Table of Contents

Cover

Title page

Copyright

Dedication

List of Contributors

Acknowledgments

Chapter 1: Introduction

Chapter 2: Neural Regeneration as a Disease-Modifying Therapeutic Strategy for Alzheimer’s Disease

Abstract

Introduction

Global health care burden of Alzheimer’s disease: epidemiological data

Etiopathogenesis of Alzheimer’s disease: what do we know?

Therapeutic approaches to Alzheimer’s disease: the promises, the failures, and the future

Neural regeneration–based therapeutic approach for AD: the rationale, the promise, and the progress

Neurotrophic factor small-molecule mimetics for Alzheimer’s disease

Enhancement of neurogenesis and memory by CNTF small-molecule mimetics

CNTF-derived neurogenic/neurotrophic compound, P021, can exert a disease-modifying effect in a transgenic mouse model of AD

Summary and conclusions

Chapter 3: Animal Models of Alzheimer’s Disease

Abstract

Introduction

The genetics of Alzheimer’s disease

Transgenic models of amyloidogenesis

Amyloid precursor protein transgenic mice

PDAPP transgenic mice

Tg2576 transgenic mice

APP23 transgenic mice

J20 transgenic mice

APP knock-in transgenic mice

APP/PS1 transgenic mice

5xFAD transgenic mice

Tau transgenic mice

Tau tg mice under tau promoter

3xTg transgenic mice

Animal models for late onset of AD

Nonmouse models

Studies in nematodes

Studies in fruit flies

Nontransgenic models for the study of AD

How to choose the right model?

Summary

Acknowledgment

Chapter 4: Mechanisms of Neuronal Microtubule Loss in Alzheimer’s Disease

Abstract

Introduction

Studies on Alzheimer’s brain and animal models

Are microtubules destabilized in the Alzheimer’s brain?

Mechanisms of microtubule loss in the Alzheimer’s brain

Strategies for treatment

Acknowledgments

Chapter 5: Tau-Centric Therapies for Treating Alzheimer’s Disease

Abstract

Introduction

Tau-centric therapeutic strategy 1: targeting tau phosphorylation

Tau-centric therapeutic strategy 2: targeting microtubule destabilization

Tau-centric therapeutic strategy 3: targeting tau aggregation

Conclusions

Chapter 6: The Potential of Small Molecules in Preventing Tau Oligomer Formation and Toxicity

Abstract

Introduction

Tau oligomers as a therapeutic target

Naturally occurring small molecules

Synthetic small molecules

Small molecules with broad antiamyloid properties

Concluding remarks

Acknowledgments

Chapter 7: A Novel Neuroprotection Target With Distinct Regulation in Stroke and Alzheimer’s Disease

Abstract

Introduction

Alzheimer’s disease

Vascular dementia

Excitotoxicity

Kidins220/ARMS

Treatments for neuroprotection in acute versus chronic excitotoxicity

Chapter 8: Sirtuin Modulation as Novel Neuroprotective Strategy for Alzheimer’s Disease

Abstract

Sirtuin protein family

Function and pathologic relevance of the mammalian sirtuins

Pharmacological activators and inhibitors of sirtuins

Sirtuins involvement in aging and longevity

Sirtuins and age-related diseases

Sirtuins and neurodegeneration

Sirtuins and Alzheimer’s disease

Chapter 9: Rescue of Neurons by Resolving Inflammation

Abstract

Introductory remark: dysfunction of prohomeostasis as a pathogenic mechanism

Inflammation and its resolution

Evidence for inflammation in Alzheimer’s disease

Chronic inflammation

Dysfunction of Resolution in Alzheimer’s Disease

Dysfunction of resolution in the nervous system and Alzheimer’s disease as a target for therapeutic intervention

Concluding remarks

Chapter 10: Targeting Transition Metals for Neuroprotection in Alzheimer’s Disease

Abstract

Introduction

Natural history of Alzheimer’s disease

Metals in the mechanisms of neurodegeneration and strategies for neuroprotection

Conclusions

Chapter 11: Multifunctional Effects of Human Serum Albumin Toward Neuroprotection in Alzheimer Disease

Abstract

Introduction

Human serum albumin

Production sites and de novo synthesis

Structure and function

Protective properties of HSA

Therapeutic approaches based on HSA

HSA implication in the dynamics of Aβ pathology

HSA as a potential therapeutic approach for AD

The interplay between ICV infusion of HSA and AD pathologies

Conclusions

Chapter 12: RGS2 and SIRT1 Link Renin Angiotensin Aldosterone System to Alzheimer’s Disease

Abstract

Need for presymptomatic AD biomarkers

Searching early AD biomarkers by peripheral blood transcriptomics

RGS2 (regulator of G-protein signaling 2)

SIRT1 (Sirtuin 1)

Alzheimer’s disease and renin-angiotensin-aldosterone system

RGS2 and SIRT1 in renin-angiotensin-aldosterone system pathways

Conclusions

Acknowledgments

Chapter 13: Neuroprotective Drug Development: The Story of ADNP, NAP (Davunetide), and SKIP

Abstract

Introduction: the discovery of ADNP

ADNP—the Alzheimer’s disease connection

NAP

SKIP

Patient stratification: ADNP as an AD diagnostic marker (Malishkevich et al., 2015b)

Epilog

Acknowledgments

Author Index

Subject Index

Copyright

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Dedication

Dedicated to the family of men and women with Alzheimer’s and to the scientists, clinicians, caretakers, and patients. With the major risk for Alzheimer’s disease being aging, it brings us back to our ancestors and to the Ten Commandments: honor thy father and mother, honor your fellow human being, and take care of the needy and elderly.

List of Contributors

D. Albani,     Department of Neuroscience, IRCCS—Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy

S. Amram

Sagol School of Neuroscience

Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel

T.O. Austin,     Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, United States

S. Ayton,     Oxidation Biology Unit, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia

P.W. Baas,     Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, United States

A.A. Belaidi,     Oxidation Biology Unit, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia

G. Biella,     Department of Neuroscience, IRCCS—Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy

A.I. Bush,     Oxidation Biology Unit, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia

F.L. Cascio

Mitchell Center for Neurodegenerative Diseases

Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, United States

C.M. Cowan,     Department of Zoology, Life Science Centre, University of British Columbia, Vancouver, BC, Canada

A. Ezra,     Department of Molecular Microbiology & Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel

D. Frenkel

Sagol School of Neuroscience

Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel

A. Gamir-Morralla

Biomedical Research Institute Alberto Sols (IIBM), Spanish Research Council—Autonomous University of Madrid (CSIC-UAM)

CIBERNED (Centre for Networked Biomedical Research in Neurodegenerative Diseases), Institute of Health Carlos III (ISCIII), Madrid, Spain

J.E. Gerson

Mitchell Center for Neurodegenerative Diseases

Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, United States

I. Gozes

The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, The Elton Laboratory for Molecular Neuroendocrinology; Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine

The Adams Super Center for Brain Studies, and Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel

D. Gurwitz

Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine

The Adams Super Center for Brain Studies, and Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel

A. Hadar,     Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

E. Hjorth,     Department of Neurobiology, Care Sciences & Society, Section of Neurodegeneration, Centre for Alzheimer’s Disease Research, Karolinska Institutet, Huddinge, Sweden

T. Iglesias

Biomedical Research Institute Alberto Sols (IIBM), Spanish Research Council—Autonomous University of Madrid (CSIC-UAM)

CIBERNED (Centre for Networked Biomedical Research in Neurodegenerative Diseases), Institute of Health Carlos III (ISCIII), Madrid, Spain

K. Iqbal,     Department of Neurochemistry, & SUNY Downstate/NYSIBR Center for Developmental Neuroscience, New York State Institute for Basic Research (NYSIBR), Staten Island, NY, United States

R. Kayed

Mitchell Center for Neurodegenerative Diseases

Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, United States

S.F. Kazim

Department of Neurochemistry, & SUNY Downstate/NYSIBR Center for Developmental Neuroscience, New York State Institute for Basic Research (NYSIBR), Staten Island

Neural and Behavioral Science Program, School of Graduate Studies, State University of New York (SUNY) Downstate Medical Center, Brooklyn, NY, United States

P. Lei,     Oxidation Biology Unit, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia

C. López-Menéndez

Biomedical Research Institute Alberto Sols (IIBM), Spanish Research Council—Autonomous University of Madrid (CSIC-UAM)

CIBERNED (Centre for Networked Biomedical Research in Neurodegenerative Diseases), Institute of Health Carlos III (ISCIII), Madrid, Spain

M. Medina

CIBERNED (Centre for Networked Biomedical Research in Neurodegenerative Diseases)

CIEN Foundation (Foundation Centre for Research in Neurological Diseases), Institute of Health Carlos III (ISCIII), Madrid, Spain

A. Mudher,     Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, United Kingdom

L. Polito,     Golgi Cenci Foundation, Milan, Italy

L. Qiang,     Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, United States

S. Quraishe,     Faculty of Medicine, University of Southampton, Southampton, United Kingdom

I. Rabinovich-Nikitin,     Department of Molecular Microbiology & Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel

P. Rabinovich-Toidman,     Department of Molecular Microbiology & Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel

M. Schultzberg,     Department of Neurobiology, Care Sciences & Society, Section of Neurodegeneration, Centre for Alzheimer’s Disease Research, Karolinska Institutet, Huddinge, Sweden

B. Solomon,     Department of Molecular Microbiology & Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel

Acknowledgments

I would like to thank all the authors for their timely response and excellent chapters. Now that the job is done, several more books may be edited, as this is an extremely dynamic field. I would also like to thank the AMN Foundation and the Israel Science Foundation for supporting my Alzheimer’s related work.

Chapter 1

Introduction

I. Gozes    The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, The Elton Laboratory for Molecular Neuroendocrinology; Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine; The Adams Super Center for Brain Studies and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel

Keywords

magnetic resonance spectroscopy

Alzheimer’s disease

amyloid

neuroprotection

creatine

gene

Searching clinicaltrials.gov for neuroprotection AND Alzheimer yielded seven results with four completed studies, of which, one has results. The study is entitled: Effects of Memantine on Magnetic Resonance (MR) Spectroscopy in Subjects at Risk for Alzheimer’s Disease (NCT00933608). Rather than concentrating on amyloid and tau, the study highlights the marked cell damage that precedes the clinical manifestation of Alzheimer’s disease (AD) and suggests that targeting populations at risk with pharmacological interventions is a possible strategy to lessen the burden of the disease.

The study population included cognitively normal individuals with subjective memory complaints with biological characteristics of early AD and family history of AD. The primary outcome of the study was change in N-acetylaspartate (NAA) measured with magnetic resonance spectroscopy (MRS). NAA is a metabolite found predominately in neuronal cells, and its amount indicates tissue well-being (the higher the better). In MRS studies, NAA (and other metabolites like choline) are presented as a ratio to creatine (Cr, internal standard) also measured by MRS. Participants took the drug once daily for 4 months. No significant change was reported. Two other studies are in their initial stages, one with low dose nicotine and one with lithium; importantly, these avenues have been previously explored, but the question is, how early should one begin?

Here, we grouped selected scientists across the globe to give us their point of view of Alzheimer’s neuroprotection, mostly from the preclinical point of view, but touching on clinical trials, each with his/her point of view. Starting from a global overview through animal models and personal prisms of interest, we travel down the path of AD neuroprotection. Gene/proteins associated with the disease are highlighted as potential new avenues for diagnostics and intervention, beyond acetylcholine esterase inhibitors, memantine, and amyloid vaccination. The more we know about the disease, the better potential for intervention, till AD becomes only a memory.

Chapter 2

Neural Regeneration as a Disease-Modifying Therapeutic Strategy for Alzheimer’s Disease

S.F. Kazim*,**

K. Iqbal*

*    Department of Neurochemistry, & SUNY Downstate/NYSIBR Center for Developmental Neuroscience, New York State Institute for Basic Research (NYSIBR), Staten Island, NY, United States

**    Neural and Behavioral Science Program, School of Graduate Studies, State University of New York (SUNY) Downstate Medical Center, Brooklyn, NY, United States

Abstract

Alzheimer’s disease (AD) is the most common age-dependent neurodegenerative disorder, which contributes significantly to the health care burden particularly in the developed world. As yet, there is no effective treatment for AD. Besides the presence of amyloid β plaques and neurofibrillary tangles, AD is characterized by neurogenic and synaptic failure leading to cognitive decline. Neural regeneration–based strategy represents a highly promising therapeutic approach for AD. Shifting the balance from neurodegeneration to neural regeneration with neurotrophic small-molecule peptide mimetics has shown promise in the animal models of AD. Our work with a ciliary neurotrophic factor–based neurogenic and neurotrophic peptidergic compound has shown that neural regeneration–based therapeutic approach can be disease modifying for AD. Human clinical trials are warranted to validate the efficacy of neural regeneration–based approach for AD.

Keywords

Alzheimer’s disease

amyloid β

tau hyperphosphorylation

neurogenesis

neuronal and synaptic plasticity

cognition

neurodegeneration

neural regeneration

ciliary neurotrophic factor (CNTF)

brain-derived neurotrophic factor (BDNF)

Introduction

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and is the most common cause of dementia worldwide (Barker et al., 2002; Cornutiu, 2015; Mayeux and Stern, 2012; Qiu et al., 2009; Reitz et al., 2011; Wilson et al., 2012). It is one of the leading causes of morbidity and mortality in the aging population (Qiu et al., 2009; Wilson et al., 2012). Short-term memory loss, that is, difficulty in remembering recent events is the most common early symptom of AD (Ballard et al., 2011; Burns and Iliffe, 2009; Cummings, 2004a). As the disease progresses, symptoms can include language problems, disorientation, mood swings, loss of motivation, poor grooming, and behavioral issues (Ballard et al., 2011; Burns and Iliffe, 2009; Cummings, 2004a). As AD advances and the cognitive function declines, the patients often withdraw from family and society. Ultimately, bodily functions are lost, leading to death.

Histopathologically, AD is characterized by two major lesions: amyloid as diffuse and neuritic plaques composed of amyloid beta (Aβ) peptide, and neurofibrillary tangles composed of hyperphosphorylated tau protein (Glenner and Wong, 1984; Grundke-Iqbal et al., 1986b). AD has also been characterized as a consequence of synaptic failure (Selkoe, 2002). In AD, synaptic loss, as reflected by alterations in the expression levels of dendritic and synaptic markers, is known to correlate better with cognitive decline than either Aβ plaque load or neurofibrillary tangles (Sze et al., 1997; Terry et al., 1991). As yet, there are no available treatments that stop or reverse the progression of AD. Currently there are also no specific markers that can confirm an AD diagnosis with a 100% certainty (Burns, 2009; Cummings, 2004b; Frisardi et al., 2010; Iqbal and Grundke-Iqbal, 2011; Iqbal et al., 2014b; Panza et al., 2009a,b, 2012).

Global health care burden of Alzheimer’s disease: epidemiological data

AD accounts for 60–80% of dementia cases (Cornutiu, 2015; Mayeux and Stern, 2012). In the United States, AD affects 5.3 million people; one in nine Americans aged 65 and older has AD (Hebert et al., 2013). AD is the sixth leading cause of death in the United States (Hebert et al., 2013). The incidence (number of new cases/year) of Alzheimer’s increases dramatically with age; in the United States, in 2015, there will be approximately 61,000 new cases among people aged 65–74; 172,000 new cases among people aged 75–84; and 240,000 new cases among people aged 85 and older (Alzheimer’s Disease Facts and Figures, 2015). Due to the increasing number of older people in the United States, the incidence of AD is projected to double by the year 2050 (Hebert et al., 2001). By 2050, the prevalence of AD is expected to nearly triple from 5.3 to 13.8 million, barring the discovery of a cure for the disease (Hebert et al., 2003,  2013).

Worldwide, nearly 47 million people have Alzheimer’s or a related dementia (Prince et al., 2015); this prevalence is expected to triple to approximately 135 million by the year 2050 (Prince et al., 2013). Alzheimer’s dementia is most common in the Western Europe (Prince et al., 2013,  2015). According to the World Alzheimer’s Report, the global societal economic cost of AD and dementia exceeded USD 600 billion in 2010, over 1% of global gross domestic product, and these costs are estimated to rise (Prince et al., 2013,  2015). According to Alzheimer’s Association, in the United States during the year 2015, AD and other dementias will cost USD 226 billion, and by 2050, these costs could rise as high as USD 1.1 trillion (Alzheimer’s Disease Facts and Figures, 2015).

Etiopathogenesis of Alzheimer’s disease: what do we know?

The German psychiatrist Alois Alzheimer described the first case of AD in 1907 [About a peculiar disease of the cerebral cortex. By Alois Alzheimer, 1907 (Translated by L. Jarvik and H. Greenson), 1987]. It was not until 1970s that AD was recognized as the most common cause of dementia and a major killer (Katzman, 1976). Although biomedical research has revealed a lot about the etiopathogenesis of AD, there is a lot yet to be discovered regarding the precise biological mechanism(s) underlying AD—why AD progresses at a much faster rate in some than others, and the possible approaches to prevent, slow, or halt the disease process (Iqbal and Grundke-Iqbal, 2011).

AD is a heterogeneous and multifactorial disorder and probably involves several different etiopathogenic mechanisms (Fig. 2.1) (Iqbal et al., 2005b;  2010;  2013;  2014b; Iqbal and Grundke-Iqbal, 2010;  2011). The familial form of AD accounts for <1% of all cases (Bird, 2008; Guerreiro and Hardy, 2014). Linkage analyses done in the early 1990s and focused on early onset AD families identified the only fully penetrant mutations known to date to be involved in this disease. Three genes were found to carry these mutations: amyloid β precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) (Bird, 2008; Goate et al., 1991; Guerreiro and Hardy, 2014; Rogaev et al., 1995; Saunders et al., 1993; Sherrington et al., 1995). Additionally, individuals who inherit one or two APOE4 alleles were identified to carry a ∼3.5- or ∼10-fold risk, respectively, of coming down with AD in different population genetics studies (Bird, 2008; Corder et al., 1993; Guerreiro and Hardy, 2014). The exact causes of the sporadic form of AD, which accounts for over 99% of the cases, are not yet understood.

Figure 2.1   Multifactorial nature of Alzheimer’s disease (AD) and involvement of several different disease mechanisms.

APP, amyloid β precursor protein; PS1, presenilin 1; and PS2, presenilin 2. Source: Modified from Iqbal, K., Grundke-Iqbal, I., 2011. Opportunities and challenges in developing Alzheimer disease therapeutics. Acta Neuropathol. 122 (5), 543–549.

Histopathologically, the sporadic and the familial forms of AD are indistinguishable from each other and both cause neurodegeneration in the brain, particularly in the hippocampus and the rest of the neocortex, which is associated with numerous extracellular deposits of amyloid β as cores of neuritic (senile) plaques and intraneuronal neurofibrillary tangles (Iqbal and Grundke-Iqbal, 2011). The seminal discoveries of amyloid β, which is seen both as plaque core and as congophilic angiopathy (Glenner and Wong, 1984; Masters et al., 1985) and of abnormal hyperphosphorylation of tau as the protein subunit of paired helical filaments (PHF) and neurofibrillary tangles (Grundke-Iqbal et al., 1986b; Iqbal et al., 1986b) were made around the same period.

In the 1990s and much of the early 2000s, the amyloid cascade hypothesis, which incriminates amyloid β as the major causative factor for tau pathology, neurodegeneration, and cognitive deficit in AD (Hardy and Higgins, 1992) gained immense popularity and remained the focus of most of the endeavors to find a cure for AD. Amyloid plaques, rampant in human AD brains, are extracellular deposits mainly composed of Aβ1–40 and Aβ1–42 which are the metabolites of APP generated by its β- and γ-secretase cleavage (Glenner and Wong, 1984; Kang et al., 1987; Masters et al., 1985). Amyloid β, though amyloidogenic, is a normal metabolite of APP. Amyloid β is catabolized by neprilysin and insulin-degrading enzyme (Miners et al., 2011). An imbalance between the rate of production and clearance of Aβ leads to its deposition as amyloid plaques. The bulk of the studies, however, suggest soluble, especially the oligomeric, Aβ as the main neurotoxic state of the peptide (Lambert et al., 1998). The earliest and strongest support for the amyloid hypothesis comes from genetic evidence. The human Down syndrome individuals, as part of trisomy 21, carry three copies of APP and almost all of them develop AD neuropathological changes by the age of 40 years (Karlinsky, 1986; Wiseman et al., 2015; Wisniewski et al., 1985).

Tau is a neuronal microtubule-associated protein. In a normal human brain, tau contains 2–3 moles phosphate per mole of the protein whereas in AD brain it is three- to fourfold hyperphosphorylated (Kopke et al., 1993). Tau is the major protein subunit of PHF, which constitute the AD neurofibrillary tangles (Grundke-Iqbal et al., 1986a; Iqbal et al., 1974). Tau in neurofibrillary tangles is abnormally hyperphosphorylated (Grundke-Iqbal et al., 1986b). Approximately 40% of the abnormally hyperphosphorylated tau in AD brain is cytosolic and oligomeric, and can be sedimented at 200,000g (Iqbal et al., 1986a; Kopke et al., 1993). Tau is a substrate for several protein kinases which include both proline-directed protein kinases (PDPKs), such as cdk5, glycogen synthase kinase-3-β (GSK3β), and Dyrk1A, and non-PDPKs, such as protein kinase A, calcium, calmodulin-activated protein kinase II, and casein-kinase I (Liu et al., 2005; Shi et al., 2008; Singh et al., 1995a,b; Wang et al., 2007). Thus, more than one combination of protein kinases can produce abnormal hyperphosphorylation of tau in AD (Wang et al., 2007). Phosphorylation of tau is mainly regulated by PP2A (Bennecib et al., 2000;  2001; Gong et al., 2000; Liu et al., 2005). The activities of several of the tau kinases are regulated by PP2A. Thus, PP2A can regulate the phosphorylation of tau both directly and by inhibiting the activities of several tau protein kinases (Iqbal et al., 2005a). PP2A activity is compromised and is probably a cause of the abnormal hyperphosphorylation of tau in AD brain (Gong et al., 1993;  1995; Liu et al., 2005).

Besides Aβ plaques and neurofibrillary tangles, AD is characterized by marked neuronal loss, failure of dentate gyrus (DG) neurogenesis, and impaired synaptic plasticity (Arendt, 2009; Crews and Masliah, 2010; Davies et al., 1987; Li et al., 2008; Scheff and Price, 2006; Scheff et al., 2006; 2007; Selkoe, 2002; Shruster et al., 2010; Sze et al., 1997; Terry et al., 1991). The process of loss of neuronal and synaptic plasticity continues unhalted in AD, and is in fact a major correlate of cognitive decline in AD (Scheff et al., 2006; Selkoe, 2002; Sze et al., 1997; Terry et al., 1991).

One of the oldest hypothesis regarding AD pathogenesis is based on cholinergic dysfunction (Barage and Sonawane, 2015; Contestabile, 2011). AD brains show reduced activity of choline acetyltransferase and acetylcholinesterase in cerebral cortex and many other areas as compared with normal brain (Bowen et al., 1976; Davies and Maloney, 1976). Many of the currently available AD drugs are based on the cholinergic dysfunction hypothesis.

Therapeutic approaches to Alzheimer’s disease: the promises, the failures, and the future

Currently, the four FDA-approved drugs, donepezil, galantamine, rivastigmine, and memantine, available for AD treatment only provide symptomatic benefit with little effect on the underlying pathology (Frisardi et al., 2010; Panza et al., 2009a,b, 2012). Obviously, there is impending urgency to find an effective disease-modifying therapy.

It is noteworthy that none of the current FDA-approved AD drugs are related to the amyloid β hypothesis and also were not tested in any transgenic AD mouse model before being implemented in the clinic (LaFerla and Green, 2012). Despite the immense popularity, the amyloid hypothesis has failed so far clinically (Morris et al., 2014). Human clinical trials utilizing Aβ-based therapies including both active and passive immunization to remove Aβ and inhibition of its synthesis and aggregation have been unsuccessful so far (for review, Giacobini and Gold, 2013; Iqbal and Grundke-Iqbal, 2010;  2011; Morris et al., 2014). In the case of active immunization, even though the Aβ plaque load was successfully decreased from the brains of AD patients, however, instead of any decrease in the rate of clinical deterioration, the treated patients showed even worse performance than the placebo-treated controls (Boche et al., 2010a,b; Fox et al., 2005; Gilman et al., 2005). A Phase III clinical trial employing passive Aβ immunotherapy found reduced Aβ pathology but failed to show any cognitive benefit (Rinne et al., 2010). As of 2015, anti-Aβ treatments have mainly failed to meet their primary clinical endpoints and some major Phase III trials had to be halted early because of the adverse effects (Morris et al., 2014). None of anti-Aβ-based treatment has shown any discernible functional recovery or altered the disease course. One of the arguments regarding the failure of Aβ-based therapeutics has been that the treatment of mild to moderate AD was probably too late and that treatment of the prodromal stage of the disease was probably required. This reasoning remains yet to be justified as the clinical trials on early stage AD are currently in progress. Nonetheless, the successive failure of Aβ-based AD therapeutics has brought the validity and foundation of amyloid cascade hypothesis into serious question (Morris et al., 2014). The amyloid hypothesis is further weakened by the fact that Aβ deposition occurs also in cognitively normal individuals; up to 40% of nondemented elderly can reach some level of neuropathological criteria for AD (Price et al., 2009).

Due to the failure of Aβ-based AD therapeutics, in recent years, tau has become a major target of studies trying to find a treatment for AD (Boutajangout and Wisniewski, 2014; Iqbal et al., 2014b; Medina and Avila, 2014; Wisniewski and Goni, 2015). Like Aβ immunotherapy, several tau transgenic mouse model studies have shown the beneficial effect of tau immunotherapy on neuropathology and neurobehavior (Asuni et al., 2007; Bi et al., 2011; Chai et al., 2011; Dai et al., 2015; Troquier et al., 2012; Yanamandra et al., 2013). The first tau immunotherapy–based Phase I vaccine trial, AADvac1, which uses a pathology-related tau peptide conjugated to KLH for active immunization, is currently in progress (Axon Neuroscience SE, www.clinicaltrials.gov). This clinical trial carries high promise as neurofibrillary tangle load and tau pathology are known to correlate better with cognitive decline in AD (Nelson et al., 2012). Given the importance of tau phosphorylation in AD a number of studies have tried inhibition of kinases involved in the process or the activation of protein phosphatase to dephosphorylate tau (for review, Boutajangout and Wisniewski, 2014; Iqbal et al., 2014b). In a small pilot study of 30 patients, Tideglusib, an inhibitor of GSK3β which is a major kinase involved in tau phosphorylation, produced positive effects on cognition without statistical significance (del Ser et al., 2013). A Phase IIb trial with Tideglusib in mild to moderate AD patients did not meet its primary end point. Inhibition of tau aggregation is another tau pathology–based potential AD therapeutic strategy which has been tested in clinical trials (Bulic et al., 2013; Wischik et al., 1996). Two Phase II clinical trials, first one utilizing a methylene blue (a tau aggregation inhibitor) derivative, Rember (TauRx Therapeutics Ltd.) and the second one using a next generation derivative, LMTX (TauRx Therapeutics Ltd.), have shown some therapeutic efficacy (Baddeley et al., 2015; Wischik et al., 2015). These clinical trials have demonstrated that targeting tau aggregation can delay the progression of cognitive decline in mild to moderate AD. TauRx is presently conducting two large Phase III clinical trials of LMTX in AD, and the results are expected in 2016. Among other tau-based therapeutics, microtubule-stabilizing agents have shown promise (Ballatore et al., 2012; Brunden et al., 2011). Davunetide (NAP), a microtubule-protecting agent has shown efficacy in amnestic mild cognitive impairment (aMCI) cases (for review, Magen and Gozes, 2013).

The multifactorial and heterogeneous nature and the likely contribution of several different etiopathogenic mechanisms make the development of effective AD therapeutics a daunting task. The development of rational AD therapeutics requires the identification of various AD subgroups as well as the determination of etiopathogenesis of each subgroup (Fig. 2.1). More importantly, developing AD therapeutic strategies that target the final common outcome of various AD subgroups, that is, neurodegeneration is required. One such highly promising therapeutic approach is shifting the balance from neurodegeneration to neural regeneration by utilizing the regenerative capacity of brain (Iqbal et al., 2014a).

Neural regeneration–based therapeutic approach for AD: the rationale, the promise, and the progress

Independent of the various etiopathogenic mechanisms involved in AD, they all lead to neurodegeneration. Thus, an effective therapeutic strategy for AD should include both inhibition of neurodegeneration and stimulation of regeneration in the brain (Fig. 2.2). This shift of balance from neurodegeneration to neural regeneration can be achieved with therapeutic strategies that enhance both neurogenesis and neuronal and synaptic plasticity (Iqbal and Grundke-Iqbal, 2010;  2011; Iqbal et al., 2014a; Kazim et al., 2014).

Figure 2.2   Two major therapeutic approaches for Alzheimer’s diseases and related neurodegenerative disorders. Source: Reproduced from Iqbal, K., Kazim, S.F., Bolognin, S., Blanchard, J., 2014a. Shifting balance from neurodegeneration to regeneration of the brain: a novel therapeutic approach to Alzheimer’s disease and related neurodegenerative conditions. Neural Regen. Res. 9 (16), 1518–1519.

Adult hippocampal neurogenesis is known to play an essential role in learning and memory (Aimone et al., 2010; Bruel-Jungerman et al., 2007; Deng et al., 2010; Sahay et al., 2011). Several studies show the involvement of adult-born hippocampal neurons in complex forms of spatial and associative memories (Abrous and Wojtowicz, 2015; Aimone et al., 2006; Drapeau et al., 2003; Dupret et al., 2008; Leuner et al., 2006; Lledo et al., 2006). AD and other neurodegenerative disorders are characterized by an imbalance between neurogenesis and neurodegeneration (Mu and Gage, 2011; Phillips et al., 2006). Age-associated decline in neurogenesis is proposed to contribute to a pathological condition and the associated learning and memory decline in AD (Li et al., 2008; Mu and Gage, 2011) and in transgenic mouse models of this disease (Demars et al., 2010; Donovan et al., 2006; Haughey et al., 2002; Wang et al., 2010).

In 3×Tg-AD mice carrying mutated human APP, tau, and PSEN1, the neurogenic decline and associated cognitive impairment happen prior to the formation of any Aβ plaques or accumulation and aggregation of abnormally hyperphosphorylated tau, suggesting that the impairment of neurogenesis might be a part of the primary pathology (Blanchard et al., 2010b). In the adult hippocampus, the survival, maturation, and integration of newborn neurons in the DG is dependent on the appropriate microenvironment (Bonfanti and Peretto, 2011; Gage, 2002; Inokuchi, 2011; Kempermann and Gage, 2000; Li et al., 2009). The microenvironment of DG in neurodegenerative disorders is adverse for the neurogenesis and the survival and the integration of newborn neurons into the hippocampal circuitry (Grote and Hannan, 2007; Verret et al., 2007a,b). Accordingly, failure of neuronal maturation and survival in DG is reported in AD (Demars et al., 2010; Jin et al., 2004; Li et al., 2008). Survival and recruitment of newborn neurons into the hippocampal circuitry is integral to hippocampus-dependent learning and memory (Aimone et al., 2006; Dupret et al., 2008; Kee et al., 2007a,b). Accordingly, the impairment in hippocampal neurogenesis adversely affects different forms of hippocampal-dependent learning, such as Morris water maze and contextual fear conditioning in rodents (Deng et al., 2009; Shors, 2008). The hippocampus is particularly vulnerable in neurodegenerative disorders. In AD, the early development of neuropathology is reported to be in hippocampal formation, and thus, as expected, the hippocampus-dependent memory impairment is reported to be one of the earliest symptoms of dementia (Belleville et al., 2008; Khan et al., 2014; Liu et al., 2012; Reitz et al., 2009; Small, 2014). Thus, any treatment which promotes formation, maturation, survival, and integration of DG granule cells can be a highly promising therapeutic approach for AD and related neurodegenerative disorders (Blanchard et al., 2010a,b, 2011; Bolognin et al., 2012; Cardenas-Aguayo Mdel et al., 2013; Chohan et al., 2011; Iqbal and Grundke-Iqbal, 2011; Iqbal et al., 2014a; Kazim et al., 2014; Kimura et al., 2009; Li et al., 2010; Wang et al., 2010).

AD has been characterized as a synaptic failure (Arendt, 2009; Selkoe, 2002). Loss of dendrites and dendritic spines has also been shown in AD (for review, Knobloch and Mansuy, 2008). Quantitative evaluation of AD brains within 2–4 years after the clinically diagnosed disease revealed a 25–35% decrease in density of synapses and a 15–35% loss in the number of synapses per neuron in the frontal and temporal cortices (Davies et al., 1987). The extent of synaptic loss is even more profound in the hippocampus where it amounts to 44–55% (Scheff et al., 1990;  2006;  2007; Scheff and Price, 2003;  2006). In fact, the most significant correlate to the severity of cognitive impairment is the synaptic loss in the frontal cortex and the limbic system (DeKosky and Scheff, 1990; DeKosky et al., 1996; Masliah et al., 1994; Terry et al., 1991). The profound loss of neurons, synapses, and dendritic arborization may contribute to impaired synaptic plasticity in AD. Altered basal synaptic transmission (decreased fEPSPs) and reduced LTP have been shown in 3×Tg-AD mice which carry mutated human APP, tau, and PSEN1 (Oddo et al., 2003). Synaptic plasticity has been proposed to be the cellular substrate of learning and memory (Neves et al., 2008). Neuronal and synaptic plasticity are the key factors in neuronal firing, neuronal recruitment into information processing networks, and ultimately learning and memory mechanisms. In the mature brain, neurogenesis is believed to play an essential role in maintaining synaptic plasticity and memory formation in the hippocampus (van Praag et al., 2002). Both AD and transgenic mouse models of AD show significant alterations in the process of neurogenesis in the hippocampus (Chevallier et al., 2005; Demars et al., 2010; Dong et al., 2004; Donovan et al., 2006; Jin et al., 2004; Wang et al., 2010; Wen et al., 2004). Thus, the synaptic plasticity impairments in AD might not only involve direct damage to the synapses, but also interference with neurogenesis.

Neurogenesis in the aging brain can be enhanced by the use of proneurogenic factors, such as neurosteroids (Karishma and Herbert, 2002; Mayo et al., 2003; Wang et al., 2010); cell cycle regulators (Molofsky et al., 2005); NMDA receptor antagonists (Nacher et al., 2003); and growth factors, such as insulin-like growth factor-1, epidermal growth factor, fibroblast growth factor-2 (FGF-2), and growth differentiation factor 11 (Aberg et al., 2000; Anderson et al., 2002; Carro et al., 2001; Jin et al., 2003; Katsimpardi et al., 2014; Lichtenwalner et al., 2001; Loffredo et al., 2013; Rai et al., 2007). Neurotrophins have also been shown to be proneurogenic in animal models of neurodegenerative disorders (for review, Dawbarn and Allen, 2003). Modulation of an immune-related factor, β2-microglobulin has also been shown to ameliorate norming aging-related impairment in neurogenesis and cognitive dysfunction (Smith et al., 2015). Taken together, all these studies show that enriching the brain biochemical milieu and microenvironment positively regulates neurogenesis. Thus senescence-related loss of new neurons is not an irreversible process, and if stimulated by appropriate factors, can be reinstituted in the aged brain.

In recent years, different strategies have been utilized to enhance neurogenesis and neuronal and synaptic plasticity in an effort to ameliorate cognitive deficits in animal models of AD. Neural stem cells–based approach to replace lost or damaged neurons in AD patients is currently the focus of intense research and seems to be a promising approach. Direct neural stem cell implantation in 3×Tg-AD mice has been shown to have a beneficial effect on cognition (Blurton-Jones et al., 2009). Pharmacological stimulation of neural stem cells with neurotrophic factors has also shown promise. Recently, FGF-2 gene transfer and brain-derived neurotrophic factor (BDNF) entorhinal cortex administration were found to have beneficial effect in relevant animal models of AD (Kiyota et al., 2011; Nagahara et al., 2009). Also, ciliary neurotrophic factor (CNTF) cell-based delivery in a mouse model of AD has been shown to prevent synaptic impairment and improvement of memory (Garcia et al., 2010).

Neurotrophic factor small-molecule mimetics for Alzheimer’s disease

The therapeutic application of neurotrophic factors, such as BDNF and CNTF is limited by poor CNS penetration, unfavorable plasma stability and pharmacokinetics, and adverse effects (Chen et al., 2001; Longo et al., 2007; Lu et al., 2013; Massa et al., 2003). Clinical trials using recombinant BDNF or CNTF have been discouraging because of multiple adverse effects and scarce bioavailability (ACTSG, 1996; Ochs et al., 2000). A highly promising strategy to overcome these shortcomings of neurotrophic factor–based drug development is to develop small-molecule peptide mimetics that could mimic the beneficial effects of neurotrophic factors on neurogenesis, neuronal and synaptic plasticity, and cognition, with suitable pharmacokinetics and blood–brain barrier (BBB) permeability and without adverse effects associated with the administration of full-length molecule (Longo and Massa, 2004;  2005;  2013; Longo et al., 2007; Massa et al., 2002;  2003; Xie and Longo, 2000).

Enhancement of neurogenesis and memory by CNTF small-molecule mimetics

CNTF is a pleiotropic cytokine and neurotrophic factor (neurokine) that plays an essential role in adult hippocampal and subventricular zone neurogenesis, and the differentiation of neural stem cells (Ding et al., 2013; Emsley and Hagg, 2003; Yang et al., 2008). CNTF belongs to the IL-6 family of cytokines, which also includes IL-11, leukemia inhibitory factor (LIF), oncostatin-M, cardiotrophin-1, and cardiotrophin-like cytokine (Senaldi et al., 1999; Shi et al., 1999). CNTF signaling occurs through a tripartite complex of CNTF receptor α (CNTFRα), LIF β receptor (LIFR), and glycoprotein 130. CNTF and LIF both signal through tyrosine phosphorylation (Tyr706) of the signal transducers and activators of transcription proteins by the membrane-associated Janus kinase (Davis et al., 1993). In the brain, CNTF is expressed in astrocytes in the neurogenic niches (Sendtner et al., 1994), while its receptor, CNTFRα, seems to be expressed predominantly in neural progenitor cells and hippocampal neurons, and various other areas of the brain including motor cortex and cerebellum (Emsley and Hagg, 2003; Sendtner et al., 1994). We have also previously shown in cell culture studies that CNTF counteracted the effect of increased FGF-2, which impairs neuronal lineage determination and maturation, resulting in promotion of successful neurogenesis (Chen et al., 2007). Overall, CNTF is the most extensively studied neurokine and its neuroprotective effects are well established (Pasquin et al., 2015). However, like other neurotrophic factors, the clinical use of CNTF is limited due to its short plasma half-life and adverse effects including anorexia, skeletal muscle loss, hyperalgesia, severe cramps, and muscle pain, upon peripheral administration in humans (ACTSG, 1996).

Previously, by using epitope mapping and by employing neutralizing antibodies to CNTF, our laboratory identified the amino acid residues 146–156 as an active region of this neurotrophic factor (Chen et al., 2007; Chohan et al., 2011). Peripheral administration with a slow release bolus implanted subcutaneously of this 11-mer CNTF peptide (Ac-VGDGGLFEKKL-NH2), named Peptide 6 (P6), for 30 days, enhanced DG neurogenesis, neuronal plasticity, and spatial reference memory of the normal adult C57Bl/6 mice (Chohan et al., 2011). P6 had a plasma half-life of over 6 h, was BBB permeable, and acted by competitively inhibiting the LIF signaling (Chohan et al., 2011).

Like AD, several transgenic mouse models of this disease show failed hippocampal neurogenesis and cognitive impairment. The triple transgenic AD (3×Tg-AD) mouse represents one of the most biologically relevant animal models of AD described so far (Oddo et al., 2003). The 3×Tg-AD mice harbor three AD-related genetic loci: human PS1M146V, human APPSWE, and human tauP301L (Oddo et al., 2003). These mice develop amyloid β plaques and neurofibrillary 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 (Oddo et al., 2003). Treatment of 6–7-month-old 3×Tg-AD mice with intraperitoneal administration of P6 for 6 weeks restored cognition by enhancing DG neurogenesis and neuronal plasticity in these animals (Blanchard et al., 2010b). Interestingly, the treatment with P6 had no detectable