Progressive and Unconventional Pharmacotherapeutic Approaches to Alzheimer’s Disease therapy

Alzheimer’s disease (AD) represents one of the most important future therapeutic targets, both with regards to basic and translational research, due to the progressive aging of most westernized countries. Estimates in 2006 indicated that the worldwide prevalence of AD was nearing 27 million cases [1] and with greater and greater proportions of the world population living beyond 60 years of age, nearly 1 in 85 people worldwide may suffer from AD in the mid-part of this century. The potential economic, social and healthcare burden of a progressive disease of this prevalence clearly presents one of the most important future threats to worldwide health. Since AD currently has no effective therapeutic cure, and it gradually renders people incapable of tending to their own needs, long-term assistive caregiving essentially is the only treatment. The need for this long-term assisted (or ‘informal’) care of AD patients also means that the social and healthcare burden also affects collateral populations and may also detrimentally affect their standard of living. A recent European Union (EU) study was created to focus upon this specific aspect of the socioeconomic burden of AD. In the 2008 Eurocode Study [2], it was estimated that 7.23 million people suffered from dementia in 27 EU countries (EU27) in 2008. The total costs of illness for dementia disorders in the EU27 was estimated to be 160 billion Euros, of which more than half was attributed to the costs of informal healthcare.

Considering the tremendous future social and economic threat posed by the increasing prevalence of AD, there are worryingly few new therapeutic strategies to effectively tackle this disease [3]. Many lines of research have focused intently upon issues such as direct disease mechanisms, but have failed thus far to generate any significant therapeutic breakthroughs. Considering the profound prevalence of AD in westernized societies, the current AD pharmacopeia is significantly lacking. Four pharmacotherapeutics are currently approved by regulatory agencies such as the U.S. Food and Drug Administration and the European Medicines Agency to treat the cognitive manifestations of AD. Reinforcing the paucity of the range of available and effective AD therapies, three of these four compounds belong to the same drug class, i.e. acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) while the other, memantine, is an N-methyl-D-aspartic acid (NMDA) receptor modulator. In contrast to this limited capacity to treat AD, a similarly prevalent disorder, i.e. hypertension, can be medicated by multiple forms of therapeutic comopounds including, diuretics (e.g. acetazolamide, amiloride), calcium channel blocking agents (e.g. amlodipine, diltiazem), angiotensin converting enzyme inhibitors (e.g. captopril, enalapril), angiotensin receptor II antagonists (e.g. losartan, valsartan), centrally-acting alpha adrenoceptor agonists (e.g. clonidine, doxazosin), catecholamine depleting agents (e.g. reserpine), beta adrenoceptor antagonists (e.g. atenolol, carvedilol) and up to eighteen different forms of combination therapeutics (e.g. amiloriode-hydrochlorothiazide, felodipine-elanapril). Therefore our range of AD therapies is seriously limited. In addition to this rather pessimistic observation, only donepezil is approved for treatment of advanced AD dementia [4]. Unfortunately the use of the anti-AD therapies in cases of mild cognitive impairment (MCI) has failed to demonstrate any significant efficacy in delaying of the onset of AD [5]. In addition to their rather limited therapeutic actions many of the currently approved AD therapies also cause physiological effects likely to reduce drug compliance, i.e. nausea, vomiting, bradycardia, decreased appetite, weight loss and increased gastric acid production and irritation. To combat this current lack of multiple efficacious anti-AD strategies, over four hundred different pharmaceutical agents are currently under investigation around the world, with nearly one hundred of these nearing the later stages of clinical review [6]. The areas of research occupied by these agents currently in development include, agents that reduce amyloid beta through vaccination processes, reduce oxidative stress via metal ion chelation or attenuate the long term inflammatory responses associated with AD [7–10].

In this Special Issue of Current Alzheimer’s Research ‘Progressive and Unconventional Pharmacotherapeutic Approaches to Alzheimer’s Disease Therapy’ we have tried to illuminate new frontiers for the prevention and treatment of AD rather than reiterate long-running fields of research. It is often the case that new and often radical changes in direction do not directly lead to ultimately effective pharmacotherapeutics, but the route by which the research has taken scientists may greatly assist successive experimentation and further AD breakthroughs. In this Special Issue we have attempted to bring together multiple diverse concepts, all targeted towards expanding our therapeutic capacity for tackling AD. We have attempted to investigate new therapeutic physiological systems, new therapeutic agents and also novel mechanistic therapeutic targets. The reviews are written by various radical thinkers in their respective fields, each of which demonstrate a fresh and potentially fruitful approach to the design of the next generation of AD therapeutics. By expanding the number of functional systems and agents that can be exploited to ameliorate the onset and progression of AD we may find additional and synergistic strategies to more effectively reduce the socio-economic burden of AD in westernized world.

NEW THERAPEUTIC SYSTEMS IN AD

Considerable evidence has been uncovered in recent years demonstrating that many central nervous system (CNS) neurodegenerative disorders, including AD, are far more complex than previously thought, e.g. physiological systems outside the CNS are often heavily implicated in central disease etiologies [11–13]. Therefore such emerging evidence emphasizes the concept that perhaps a more efficacious series of anti-AD agents can be generated that attenuate deleterious biological functions common to both the central nervous system (CNS) and the periphery [14]. Among one of the most important peripheral physiological systems that appears to be connected to AD etiology is that of energy expenditure and somatic metabolism. Significant energy metabolic dysfunctions have been observed in both AD human patients as well as murine transgenic models of AD [15–17]. In this Special Issue, the position of considering energy expenditure and metabolic systems as potential AD therapeutic targets has been covered by three leading scientists in this new field of neurological research. Firstly Dr. Bronwen Martin’s group at the NIH-National Institute on Aging (Cai et al) has investigated the complex interface between multiple neurodegenerative disorders, including AD, and the global metabolic system in both humans and experimental animals. In this review Dr. Martin’s group identify significant commonalities between AD and other forms of neurodegeneration, that concern hormones and trophic factors strongly linked with both metabolic actions at multiple sites in the body including the pancreas, tongue, gut, cardiovascular system and CNS [18–24]. Such connectivity between these functionally-related hormones may be indicative of ‘higher-order’ chemical relationships that connect multiple, coordinated systems in both health and disease. In a complementary piece, Dr. Suzanne de la Monte of Brown University discusses, in a focused manner the role of CNS insulin resistance in AD etiology and pathophysiology. In this review Dr. de la Monte expertly outlines the evidence linking the multifactorial event of insulin resistance to AD and the alterations of glucose metabolism that are present in this condition [25, 26]. This review therefore covers the concept that AD itself could represent a type of centrally-targeted diabetes mellitus-type condition. This review then employs this concept and considers the relative therapeutic merits of different anti-diabetic agents to combat this central AD-related insulin resistance syndrome. A third review in this section of the Special Issue, from Dr. Alexis Stranahan and colleagues of the Medical College of Georgia, also investigates how energy metabolic functions interact with AD but from quite a different perspective. This review attempts to appreciate how the metabolic and stress-related responses to physical exercise can productively interact with AD pathophysiology to bring about beneficial neurotrophic and neuroprotective actions. This physiological and behavioral intervention is discussed in detail to uncover the relative contribution of the multiple exercise-modulated physiological and metabolic systems to the eventual AD-therapeutic actions. Such knowledge can itself then lead to the generation of pharmacotherapeutics that can physiologically exploit this information to generate a ‘pharmaco-mimesis’ of the behavioral intervention [27]. Therefore taking together collated data in these three review articles, it is clear that therapeutic interventions based upon normalization of somatic or central energy regulatory mechanisms could likely form a strong therapeutic core for future AD pharmacopeia.

NEW THERAPEUTIC AGENTS FOR AD

As previously stated there are currently many new forms of AD therapeutic compounds under consideration for potential use. While the study of chemical agents with ever more specific functionalities may yield important breakthroughs, perhaps it may be prudent to consider parallel research into chemical groups that contain agents with pluripotent pharmacological activities. In this part of our Special Issue we have combined manuscripts covering both traditional hormonal and ethnobotanical compounds, as well as familiar pluripotent experimental compounds applied through a novel route of administration.

In the first of these reviews Drs. Melanie-Jayne Howes and Peter Houghton of the Royal Botanical Gardens at Kew and King’s College London respectively, assess the potential ethnobotanical contribution to the AD pharmacopeia. In this case, botanical compounds may be directly employed as therapeutics, or may serve to provide insights into the development of radical new agents based on the lead botanical chemical structures. Such an approach has already proved clinically efficacious as two existing AD pharmacotherapeutics, rivastigmine and galantamine, were both derived from ethnobotanical compounds [28, 29]. In this review, an in-depth consideration of the therapeutic merits of several major species, e.g. Crocus, Ginkgo and Salvia, is given. While botanical agents are often considered too non-specific to be effective pharmacotherapeutics, it is likely that for highly complex, neural network-dependent disorders such as AD, a manageable form of polypharmacology may present the best mechanism to subtly re-adjust the multifactorial pathology [30, 31]. In addition to the appreciation of pluripotent botanical agents, the second review in this section, from Dr. Jenna Carroll of the University of Pennsylvania, also considers the therapeutic potential of drugs based around the core structure of the sex steroid hormones. Naturally these simple steroid hormones possess an enormous range of physiological activities, both centrally and peripherally. Indicative of the profound connectivity between the sex steroid system and AD pathology, multiple reports have associated the deterioration of the reproductive system with pathophysiological aging and AD itself [32–34]. In this manuscript Dr. Carroll discusses the roles of steroidal hormones in the generic pathophysiology of AD as well as their actions upon the specific amyloid- and tau-mediated toxic effects. Bearing this in mind, it is clear that pharmacological modulation of the levels or functionality of these pluripotent hormones may be a tractable AD strategy. To this end, direct hormone therapy as well as the use of selective estrogen/androgen receptor modulators in AD is thoughtfully addressed. Forming a therapeutic bridge between this review and the previous ethnobotanical review is the demonstration of the potential benefits for AD treatment of phyto-steroidal agents such as genistein and daidzein [35, 36].

The final review in this section also intersects with the therapeutic sphere of botanical agents as well as the pluripotent effects of steroidal compounds. In the case of AD pathophysiology it has been demonstrated that chronic inflammatory activities are present and could significantly contribute to the etiology of the disorder [37]. Potent anti-inflammatory actions of both sex steroid agents and botanical extracts has already been demonstrated that may contribute their anti-AD efficacy [38, 39]. One of the most important breakthroughs in the field of inflammatory disorders, in which one could rank AD, is the development of ‘biologic’ agents such as etanercept [40]. Etanercept is a highly complex pharmacological compound (marketed as Enbrel) generated through recombinant DNA technology. The complete active agent comprises a fusion product between the soluble Type 2 human tumor necrosis factor (TNF) receptor with the Fc component of human immunoglobulin G1 (IgG1). TNF acts a potent inflammatory agent in many physiological processes, both in the CNS and the periphery, and its therapeutic potential in AD has recently become a topic of intense interest [41]. Etanercept once introduced to a biological scenario where excess inflammatory TNF is present can act as a molecular sponge for this agent and thus effectively attenuate potentially detrimental inflammatory functions. In the final review in this section one of the pioneers of the use of etanercept to reduce inflammatory behavior in AD [42], Dr. Edward Tobinick of the University of California Los Angeles, illustrates the potential effects of a novel mode of etanercept treatment for AD. Dr Tobinick discusses both the traditional application process of etanercept for the remediation of AD and also assesses the efficacy of a novel mode of administration, i.e. perispinal introduction. The use and future benefits of this novel form of ‘biologic’ administration in the setting of AD is thoroughly discussed in this review as well as the impact of this form of drug delivery for CNS-targeted agents.

NEW THERAPEUTIC TARGETS IN AD

In the final section of this Special Issue, radical new AD therapeutic targets are considered and reviewed. As stated previously, despite the huge worldwide prevalence of the disease and the existence of over 76,000 articles published in PubMed concerning Alzheimer’s disease, our current AD pharmacopeia is worryingly small. Therefore, perhaps a revision of our idea of what drug targets can be may help with such a quandary. The development of AD therapies targeted towards classical targets such as transmembrane receptors, ion channels or synthetic enzymes currently seems incredibly un-productive. In the final two reviews, Dr. Wayne Chadwick of Takeda Pharmaceuticals (U.K.) and colleagues, along with Dr. Alexis Stranahan (Georgia Health Sciences University), consider the therapeutic potential of directing AD drug discovery to two distinct and novel targets. In the first review, Dr. Chadwick considers that once one acknowledges the crucial role of endoplasmic reticular function in AD, the targeting of therapies towards this ‘non-classical’ target seems logical. The endoplasmic reticulum (ER), as an organelle may represent a ‘keystone’ in the signaling networks involved in the cellular pathology of AD. Dr. Chadwick indicates how the enormous functional interface between the ER and AD pathophysiology makes the drug-mediated control of this organelle a potentially important future therapeutic strategy. As so many of the activities of the ER synergize to regulate AD pathology, e.g. protein folding and accumulation, calcium modulation and vesicular trafficking, even a modest rectification of normal ER function in AD may combine to generate a significant ‘self-reinforcing’ therapeutic effect. In addition to the consideration of the ER cellular system as an AD therapeutic target, Dr. Stranahan investigates the utility of controlling the cellular clock system [43] as a novel therapeutic strategy. As the most important risk factor for AD is aging, it seems likely that a strong functional connection between the age-monitoring functions of the cellular clock systems exists. Not only is the cellular clock system associated with cellular functions such as long-term potentiation, that are crucial for memory formation, but also circadian rhythm processes may affect the disposition and metabolism of more classical AD therapeutic agents as well. Therefore an appreciation of the effects of circadian rhythm and the processes of cell aging may not only present new molecular targets for AD therapeutics, but may also aid with the enhancement of the efficacy of other pharmacotherapeutic molecules.

It is clear that we need to start thinking creatively about new ways of treating AD. The health and economical burden of AD in aging populations can not be underestimated and increased funding and research is necessary to find new treatments for this devastating disorder. Even if novel therapeutic agents created from the research associated with these unconventional approaches do not eventually transform into functional treatments, our appreciation of AD pathophysiology is likely to be greatly enhanced.