Volume 15, Number 2, October 2008 - Special Issue "Novel Approaches to Alzheimer’s Disease Therapeutics" (Guest Editor: Muhammad Omar Chohan)

Pages 155-156
Muhammad Omar Chohan
Foreword: Novel Approaches to Alzheimer's Disease Therapeutics

Pages 157-168
Einar M. Sigurdsson
Immunotherapy Targeting Pathological Tau Protein in Alzheimer’s Disease and Related Tauopathies
Abstract: Immunotherapies that target the amyloid-β (Aβ) peptide in Alzheimer's disease (AD) have shown promise in animal and human studies. Although the first clinical trial was halted because of adverse reactions, this approach has been refined and additional trials are underway. Another important target in AD is the neurofibrillary tangles, composed primarily of hyperphosphorylated tau proteins, which correlate well with the degree of dementia. As Aβ and tau pathologies are likely synergistic, targeting both should be more effective and may be essential as early diagnosis prior to cognitive decline is currently not available. Also, Aβ immunotherapy only results in a very limited indirect clearance of tau aggregates in dystrophic neurites, showing the importance of developing a separate therapy that directly targets pathological tau. Our findings in two tangle mouse models indicate that immunization with a phospho-tau derivative reduces aggregated tau in the brain and slows progression of the tangle-related behavioral phenotype. These antibodies enter the brain and bind to pathological tau within neurons. We are currently clarifying further the mechanism of action of this promising therapeutic approach and determining its epitope specificity.

Pages 169-179
Norbert Zilka, Eva Kontsekova, Michal Novak
Chaperone-like antibodies targeting misfolded tau protein: New vistas in the immunotherapy of neurodegenerative foldopathies
Abstract: Neurodegenerative foldopathies are characterized by aberrant folding of proteins leading to the intracellular and extracellular accumulation of insoluble misfolded proteins. One of the most prominent protein folding disorders is Alzheimer’s disease (AD). In AD, there were identified two major driving forces behind neurodegeneration, misfolded proteins tau and amyloid-β. Tau belongs to a family of intrinsically disordered proteins that are characterized by the absence of a rigid three-dimensional structure in their natural environment. However, in disease condition, tau truncation and hyperphosphorylation could lead to tau transformation from intrinsically disordered protein into highly ordered soluble and insoluble misfolded structures. Increased understanding of the molecular mechanism underlying pathological transformation of tau protein has opened up the possibility of targeting misfolded tau for therapeutic purpose. Pharmacological research has identified several therapeutic approaches targeting directly or indirectly tau cascade. Novel promising field of AD treatment represent monoclonal antibodies with chaperon like activities that will be able to neutralize the toxic gain of function of misfolded tau and thus increase its degradation. We suggest that chaperon like antibodies targeting disease modified tau may hold promise for the successful treatment of AD and related foldopathies.

Pages 181-191
Ana Martinez and Daniel I. Perez
GSK-3 Inhibitors: A Ray of Hope for the Treatment of Alzheimer’s Disease?
Abstract: Alzheimer’s disease (AD) is the most common form of dementia affecting more than 15 millions individuals worldwide. While the cause is unknown, there are two major neuropathological abnormalities present in the brains of patients with AD, the extracellular senile plaques and the intracellular neurofibrillary tangles. There is strong evidence that glycogen synthase kinase-3 (GSK-3) plays an important role in AD being involved in the regulation of these neuropathological hallmarks. Increased activity and/or overexpression of this enzyme in AD is associated with increased tau hyperphosphorylation and alterations in amyloid-β processing that are thought to precede the formation of neurofibrillary tangles and senile plaques, respectively. Moreover, over activity of GSK-3 is also involved in neuronal loss. These data clearly identify GSK-3 inhibitors as one of the most promising new approaches for the future treatment of AD and a reduction of the aberrant over activity of this enzyme might decrease several aspects of the neuronal pathology in AD. In this review, we provide an overview of the rationale for the development of GSK-3 inhibitors for the treatment of AD, discussing the risks and benefits of this approach.

Pages 193-198
Beka Solomon
Filamentous Bacteriophage as a Novel Therapeutic Tool for Alzheimer’s Disease Treatment
Abstract: Antibodies towards the N-terminal region of the amyloid-β peptide (Aβ) bind to Aβ fibrils, leading to their disaggregation. We developed an immunization procedure using filamentous phages displaying the only four amino acids EFRH encompassing amino acids 3-6 of the 42 residues of Aβ, found to be the main regulatory site for Aβ formation. Phages displaying EFRH epitope are effective in eliciting humoral response against Aβ which, in turn, relieves amyloid burden in brains of amyloid-β protein precursor transgenic mice, improving their ability to perform cognitive tasks. In order to overcome the low permeability of the blood brain barrier for targeting 'anti-aggregating' monoclonal antibodies (mAbs) to Aβ plaques in the brain, we applied antibody engineering methods to minimize the size of mAbs while maintaining their biological activity. Single-chain antibodies displayed on the surface of filamentous phage showed the ability to enter the central nervous system (CNS). The genetically engineered filamentous bacteriophage proved to be an efficient, nontoxic viral delivery vector to the brain, offering an obvious advantage over other mammalian vectors. The feasibility of these novel strategies for production and targeting of anti-aggregating antibodies against Aβ plaques to disease affected regions in the CNS may have clinical potential for treatment of Alzheimer's disease.

Pages 199-210
Michael W. Marlatt, Paul J. Lucassen, George Perry, Mark A. Smith and Xiongwei Zhu
Alzheimer’s Disease: Cerebrovascular Dysfunction, Oxidative Stress, and Advanced Clinical Therapies
Abstract: Many lines of independent research have provided convergent evidence regarding oxidative stress, cerebrovascular disease, dementia, and Alzheimer’s disease (AD). Clinical studies spurred by these findings engage basic and clinical communities with tangible results regarding molecular targets and patient outcomes. Focusing on recent progress in characterizing age-related diseases specifically highlights oxidative stress and mechanisms for therapeutic action in AD. Oxidative stress has been investigated independently for its relationship with aging and cardiovascular and neurodegenerative diseases and provides evidence of shared pathophysiology across these conditions. The mechanisms by which oxidative stress impacts the cerebrovasculature and blood-brain barrier are of critical importance for evaluating antioxidant therapies. Clinical research has identified homocysteine as a relevant risk factor for AD and dementia; basic research into molecular mechanisms associated with homocysteine metabolism has revealed important findings. Oxidative stress has direct implications in the pathogenesis of age-related neurodegenerative diseases and careful scrutiny of oxidative stress in the CNS has therapeutic implications for future clinical trials. These mechanisms of dysfunction, acting independently or in concert, through oxidative stress may provide the research community with concise working concepts and promising new directions to yield new methods for evaluation and treatment of dementia and AD.

Pages 211-222
Silvia A. Mandel, Tamar Amit, Limor Kalfon, Lydia Reznichenko, Orly Weinreb and Moussa B.H. Youdim
Cell Signaling Pathways and Iron Chelation in the Neurorestorative Activity of Green Tea Polyphenols: Special Reference to Epigallocatechin Gallate (EGCG)
Abstract: Although much progress has been made in understanding the pathogenesis of Alzheimer's disease (AD), the current therapeutic approaches are merely symptomatic, intended for the treatment of cognitive symptoms, such as disturbances in memory and perception. Novel promising strategies suggest the use of anti-inflammatory drugs, antioxidants including natural occurring plant flavonoids, iron-complexing molecules, neurotrophic factor delivery, inhibitors of the amyloid-β protein precursor processing secretases, γ and β, that generate amyloid-β peptides and the interference with lipid and cholesterol metabolism. Human epidemiological and new animal data suggest that tea drinking may decrease the incidence of dementia, AD and Parkinson’s disease. In particular, its main catechin polyphenol constituent (-)-epigallocatechin-3-gallate (EGCG) has been shown to exert neuroprotective/neurorescue activities in a wide array of cellular and animal models of neurological disorders. This review provides a detailed overview on the multimodal activities of green tea polyphenols with emphasis on their iron chelating, neurorescue/neuroregenerative and mitochondrial stabilization action.

Pages 223-240
Ashley I. Bush
Drug Development Based on the Metals Hypothesis of Alzheimer’s Disease
Abstract: The recent report of positive results from a Phase IIa clinical trial of PBT2, a novel drug that targets amyloid-β-metal interactions, underscores the value of abnormal transition metal metabolism as potential therapeutic target in Alzheimer’s disease. The Metals Hypothesis of Alzheimer’s disease is based upon observations of the precipitation of amyloid-β by zinc and its radicalization by copper. Both metals are markedly enriched in plaques. The Hypothesis involves the perturbance of these endogenous brain metals, and it does not consider toxicological exposure part of pathogenesis. Recent descriptions of the release of ionic zinc and copper in the cortical glutamatergic synapse, modulating the response of the NMDA receptor, may explain the vulnerability of amyloid-β to abnormal interaction with these metal ions in the synaptic region leading to aggregation and fostering toxicity. Increasingly sophisticated medicinal chemistry approaches are being tested which correct the abnormalities without causing systemic disturbance of these essential minerals. PBT2, clioquinol and related compounds are ionophores rather than chelators. PBT2, is a once per day, orally bioavailable second generation 8-OH quinoline derivative of clioquinol. It has performed very satisfactorily in toxicology and Phase I clinical trials and is advancing as a disease-modifying candidate drug for Alzheimer’s disease.

Pages 241-254
Kiminobu Sugaya and Stephanie Merchant
How to Approach Alzheimer’s Disease Therapy Using Stem Cell Technologies
Abstract: The use of stem cells for neuroreplacement therapy is no longer science fiction - it is science fact. We have succeeded in producing neural cells in the brain using both neural and mesenchymal stem cell transplantation and even systemic injection using a small molecular compound. We have seen the improvement of cognitive function in animal models following the application of these stem cell technologies. These results may promise a bright future for stem cell based neuroreplacement therapies for neurodegenerative diseases including Alzheimer’s disease (AD). However, we have to consider the pathophysiological environments of individual diseases before clinical applications can be introduced. We must find the factors in the pathology that may affect stem cell biology and overcome the negative effects on neuroreplacement. Here, we discuss not only the potential for therapeutic applications of stem cell strategies in neuropathological conditions, but also how to overcome the adverse effects on the biology of stem cells due to the factors that are altered under AD pathology.

Pages 255-283
Antonino Cattaneo, Simona Capsoni and Francesca Paoletti
Towards Non Invasive Nerve Growth Factor Therapies for Alzheimer’s Disease
Abstract: In the past thirty years, nerve growth factor (NGF) has received much attention for its potential role as a therapeutic agent for Alzheimer’s disease (AD) due to its neurotrophic activities on basal forebrain cholinergic neurons. This attention has been renewed by recent findings that provide new causal links between defects in NGF signaling, transport or processing to the activation of the amyloidogenic route and, more generally, to AD neurodegeneration. Thus, the concept of therapeutic administration of human recombinant NGF in AD patients has a strong rationale, being further validated by recent and ongoing clinical trials with a gene-therapy approach. However, the widespread clinical application of gene-or cell-therapy strategies for the delivery of NGF to AD patients seems unpractical, and it would be more advantageous to have non-invasive methods, that should also limit the adverse effects of NGF in activating nociceptive responses. This review will describe: 1) the data from preclinical and clinical studies underlying the rationale of NGF as a potential therapeutic agent for AD; and 2) the alternative strategies to reach adequate concentrations of NGF in relevant brain areas while preventing the onset of adverse effects.

Paes 285-287
Saad Shafqat
Alzheimer Disease Therapeutics: Perspectives from the Developing World
Abstract: Although a majority of dementia patients live in middle-income and low-income countries, dementia represents an under-recognized public health burden in the developing world. Culturally and socially, it tends to be trivialized as an inevitable consequence of aging. Economic constraints are paramount, precluding the availability of institutionalized elder care and a state-sponsored health care system. Evidence-based practice for the management of dementia is also hampered by lack of a clear-cut expert consensus on the efficacy of anti-dementia drugs. Public health education, substantial health infrastructure development, and therapeutic advances are necessary for the developing world’s looming dementia crisis to be adequately tackled.

Pages 289-301
Bruno Vellas, Nicola Coley and Sandrine Andrieu
Disease Modifying Trials in Alzheimer’s Disease: Perspectives for the Future
Abstract: Disease modifying trials are becoming increasingly common in the field of Alzheimer’s disease (AD) as the search for a treatment able to slow the progression of this disease continues. In this paper, we briefly discuss the methodological considerations for disease modifying trials that were addressed during three recent international task force meetings involving specialists in the field of AD trials. Topics covered included study design, the identification of appropriate outcomes, the use of biomarkers, and the identification of suitable study populations. We also provide an update on recent disease modifying trials which have enabled us to gain experience in the use of biomarkers and have helped to define suitable outcomes, and consider how they can help us to shape future perspectives for disease modifying trials.

Pages 303-325
Robert E. Becker, Nigel H. Greig, Ezio Giacobini
Why Do So Many Drugs for Alzheimer’s Disease Fail in Development? Time for New Methods and New Practices?
Abstract: Alzheimer’s disease (AD) drug developments and clinical trials (CT) remain vulnerable to problems that undermine research validity. Investigations of CT methods reveal how numerous factors decrease active drug-placebo group differences and increase variance, thereby reducing power to reach statistical significance for outcome measure differences in AD CTs. Such factors include, amongst many, inaccuracy, imprecision, bias, failures to follow or lack of operational protocols for applying CT methods, inter-site variance, and lack of homogeneous sampling using disorder criteria. After a review of the literature and survey of a sample of AD and Mild Cognitive Impairment (MCI) CTs, the authors question whether problems of human error preclude AD researchers from continuing their dependence on rated outcome measures for CTs. The authors propose that the realities of AD, especially a probable irreversible progression of neuropathology prior to onset of clinical symptoms or signs capable of differentiating persons at risk for AD from normal aged, require AD investigators and clinicians to privilege biomarkers and encourage their development as surrogate targets for preventive AD treatment developments, testing, and use in clinical practice.

Pages 327-338
Cynthia M. Carlsson
Lessons Learned from Failed and Discontinued Clinical Trials for the Treatment of Alzheimer’s Disease: Future Directions
Abstract: While advances have been made in understanding the neurobiological processes underlying Alzheimer’s disease (AD), few treatment options currently exist. Numerous potential therapeutic and/or preventive agents have been tested in clinical trials, yet most have failed to show a clear therapeutic benefit. The lack of effective medical therapies coupled with the incipient projected dramatic increase in the number of persons with AD in the coming decades has put medical research in a crisis to urgently find effective treatment and prevention strategies. Researchers and funding agencies have been rethinking investigative approaches in order to accelerate scientific discovery in AD therapeutics, including methodological issues in the design and implementation of clinical trials. This review discusses lessons learned from discontinued and failed clinical trials for the treatment and prevention of AD with an emphasis on future directions of AD clinical trials. In particular, attention is given to choice of study outcome measures, participant selection and retention, and clinical trial design. While there are few treatments available for AD currently, the potential for discovery over the next decade is promising.

Pages 339-345
Khalid Iqbal, M. Omar Chohan, and Inge Grundke-Iqbal
Stratification of Patients is the Way to Go to Develop Neuroprotective/Disease-Modifying Drugs for Alzheimer’s Disease
Abstract: Development of effective neuroprotective drugs for Alzheimer’s disease (AD) is a formidable challenge because this disease is multifactorial and heterogeneous. Although AD is characterized histopathologically by the presence of numerous amyloid-β plaques and neurofibrillary degeneration of abnormally hyperphosphorylated tau in the brain, these two hallmark lesions do not exist in any fixed proportion in this disease. Furthermore, in the brains of some normal aged individuals, there are as many amyloid-β plaques seen as in typical cases of AD. On the other hand, extensive neurofibrillary degeneration of abnormally hyperphosphorylated tau and dementia but in the absence of amyloid-β plaques occur in several related neurodegenerative disorders called tauopathies. More than one molecular mechanism has been described for the development of amyloid-β as well as neurofibrillary degeneration of abnormally hyperphosphorylated tau. Thus, AD apparently results from several different etiopathogenic mechanisms and offers numerous rational therapeutic targets. We have discovered that there are at least five different subgroups of AD, and future studies are likely to identify additional subgroups. The employment of these subgroups of AD in clinical trials can markedly increase the success in developing specific and potent therapeutic drugs.

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