The value and limitations of transgenic mouse models used in drug discovery for Alzheimer's disease: an update

INTRODUCTION: The exponential growth in the world's aged population has increased pressure on drug discovery efforts to identify innovative therapies for Alzheimer's disease (AD). The long and uncertain clinical trial path utilized to test the potential efficacy of these novel agents is challenging. For these and other reasons, there has been an explosion in the generation and availability of transgenic mouse models that mimic some, but not all aspects of AD. The largely overwhelmingly positive results obtained when testing potential clinical agents in these same animal models have failed to translate into similar positive clinical outcomes. AREAS COVERED: This review discusses the value and limitations associated with currently available transgenic mouse models of AD. Furthermore, the article proposes ways in which researchers can better characterize pharmacodynamic and pharmacokinetic endpoints to increase the success rate for novel therapies advancing into clinical development. Lastly, the author discusses ways in which researchers can supplement, expand and improve transgenic mouse models used in AD drug discovery. EXPERT OPINION: The use of transgenic mouse models that recapitulate various aspects of AD has expanded our knowledge and understanding of disease pathogenesis immensely. Further success in testing and translating novel therapies from animal models into bona fide medicines would be enhanced by i) the availability of better models that more fully recapitulate the disease spectrum, ii) defining and measuring standardized endpoints that display a pharmacodynamic range, iii) building and including translatable biomarkers and iv) including novel endpoints that would be expected to translate into clinically beneficial outcomes.     

An update on the efficacy of non-steroidal anti-inflammatory drugs in Alzheimer's disease

Several epidemiological studies suggest that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD), especially for patients carrying one or more ?4 allele of the apolipoprotein E. The biological mechanism of this protection is not completely understood and may involve inhibition of COX activity, inhibition of β-amyloid_1-42 (Aβ42) production and aggregation, inhibition of β-secretase activity, activation of PPAR-γ or stimulation of neurotrophin synthesis. Unfortunately, long-term, placebo-controlled clinical trials with both non-selective and COX-2 selective NSAIDs in AD patients produced negative results. A secondary prevention study with rofecoxib in patients with mild cognitive impairment and a primary prevention study with naproxen and celecoxib in elderly subjects with a family history of AD were also negative. All these failures have diminished the hope that NSAIDs could be beneficial in the treatment of AD. It is hypothesized that the chronic use of NSAIDs may be beneficial only in the normal brain by inhibiting the production of Aβ42. Once the Aβ deposition process has started, NSAIDs are no longer effective and may even be detrimental because of their inhibiting activity on activated microglia of the AD brain, which mediates Aβ clearance and activates compensatory hippocampal neurogenesis.     

Increasing the success rate for Alzheimer's disease drug discovery and development

This paper responds to the fact that over 200 Alzheimer's disease (AD) drug candidates have failed to date and draws on searches of the literature for studies of error effects in drug developments and the authors' published works. In the same period, basic knowledge of AD pathology has greatly expanded providing both potential therapeutic targets and rationales for modifications in strategies for testing AD drug candidates. Current opinion generally holds that AD drug candidates have failed because they address pathology that is already too advanced. Less attention is paid to numerous reported methodological weaknesses capable of biasing AD clinical trials and drug developments and thus invalidating conclusions to be reached about the drugs being tested. The costs of quality controls possibly needed to better insure validity in AD drug developments raises concerns that progress toward success in AD drug development may be hindered by the costs of intervening against current methodological barriers to the successful completions of AD drug developments.     

Using Drosophila models of neurodegenerative diseases for drug discovery

Introduction: Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease are increasing in prevalence as our aging population increases in size. Despite this, currently there are no disease-modifying drugs available for the treatment of these conditions. Drosophila melanogaster is a highly tractable model organism that has been successfully used to emulate various aspects of these diseases in vivo. These Drosophila models have not been fully exploited in drug discovery and design strategies.

Areas covered: This review explores how Drosophila models can be used to facilitate drug discovery. Specifically, we review their uses as a physiologically-relevant medium to high-throughput screening tool for the identification of therapeutic compounds and discuss how they can aid drug discovery by highlighting disease mechanisms that may serve as druggable targets in the future. The reader will appreciate how the various attributes of Drosophila make it an unsurpassed model organism and how Drosophila models of neurodegeneration can contribute to drug discovery in a variety of ways.

Expert opinion: Drosophila models of human neurodegenerative diseases can make a significant contribution to the unmet need of disease-modifying therapeutic intervention for the treatment of these increasingly common neurodegenerative conditions.     

Rivastigmine: an update on therapeutic efficacy in Alzheimer's disease and other conditions

SUMMARY

The results of recent clinical trials with rivastigmine show that in the approved indication of mild to moderate Alzheimer's disease (AD), the drug is effective in the long term. Rivastigmine produces a significant delay in the decline of the three components of AD that have been identified by European guidelines as essential parameters for the assessment of therapeutic efficacy of medicinal products with this indication. These are cognitive function, the ability to perform the usual activities of daily living, and global judgement of the patient's condition by the patient himself, his caregiver and his doctor. Moreover, rivastigmine produces significant control of AD behavioural disorders. This further reduces caregiver burden, reduces the probability of institutionalisation, and enables the reduction or discontinuation of expensive and poorly tolerated antipsychotics. Recent trials also suggest that rivastigmine is effective in moderate to severe Alzheimer's disease, 'mixed' dementia (AD associated with vascular disorders) and Lewy body dementia. Preliminary investigations have also indicated that the drug may provide important benefits in patients with vascular dementia or dementia associated with Parkinson's disease. Pharmacoeconomic studies show that the therapeutic properties of rivastigmine result in economic savings for the care of demented patients living in the community.     

Non-cholinergic drug development for Alzheimer's disease

Background: Recent advances in the understanding of the pathobiology of Alzheimer's disease have led to a large number of non-cholinergic targets for the development of therapeutic agents. These include, for example, neurotransmitter-based, anti-amyloid, antitangle, antioxidant, anti-excitotoxic, and growth factor strategies. There are several hundred agents in, or approaching, clinical trials. Some hold promise for treatment of those affected, some may have potential for prevention, some for both. Objectives: Key examples of each of these development approaches will be summarized. Conclusions: It is too soon to predict which, if any, of these approaches will bear fruit. At the moment, it appears that the amyloid-based therapies are the farthest along in development, and have shown in some cases that the amyloid dysregulation cascade can be interrupted. It is unknown, however, whether altering this aspect of the pathobiology of Alzheimer's will actually yield clinical benefit. Efforts to affect tangle development would appear to be a fruitful approach, although these efforts lag behind the anti-amyloid efforts. The same is essentially true for the other approaches reviewed as well. Given the fact that many new interventions target specific pathways that can be measured biologically in go–no go proof of concept studies, the opportunity exists to capitalize on biomarkers in earlier stages of development. The same can be said for evolving imaging techniques. Given the number of agents in development, we offer the provocative suggestion that the biggest threat to identifying effective therapies may prove to be the implementation of enough treatment trials, and applying out-of-the-box prevention methodologies, rather than the discovery of promising candidates. This prediction may or may not hold true.     

Behavioral assays with mouse models of Alzheimer's disease: Practical considerations and guidelines

In Alzheimer's disease (AD) basic research and drug discovery, mouse models are essential resources for uncovering biological mechanisms, validating molecular targets and screening potential compounds. Both transgenic and non-genetically modified mouse models enable access to different types of AD-like pathology in vivo. Although there is a wealth of genetic and biochemical studies on proposed AD pathogenic pathways, as a disease that centrally features cognitive failure, the ultimate readout for any interventions should be measures of learning and memory. This is particularly important given the lack of knowledge on disease etiology – assessment by cognitive assays offers the advantage of targeting relevant memory systems without requiring assumptions about pathogenesis. A multitude of behavioral assays are available for assessing cognitive functioning in mouse models, including ones specific for hippocampal-dependent learning and memory. Here we review the basics of available transgenic and non-transgenic AD mouse models and detail three well-established behavioral tasks commonly used for testing hippocampal-dependent cognition in mice – contextual fear conditioning, radial arm water maze and Morris water maze. In particular, we discuss the practical considerations, requirements and caveats of these behavioral testing paradigms.     

Progress in acetylcholinesterase inhibitors for Alzheimer's disease: an update

Background: To date, the pharmacotherapy of Alzheimer's disease (AD) has been based on acetylcholinesterase inhibitors (AChEIs), and more recently on an N-methyl-d-aspartate receptor antagonist. By increasing acetylcholine concentration in the brain, AChEIs slow behavioral and functional impairments, improving cognitive function. Objective: The review provides an update on novel analogs of approved AChEIs, their combination with other anti-AD agents, natural AChEIs, and modern multitarget-directed ligands (MTDLs) able to hit different biological targets. Methods: We reviewed patents filed during 2005 – 2007 dealing with new AChEIs and their potential application for AD treatment. We point out new chemical structures and scaffolds for designing new AD therapeutic agents as well as new combinations or MTDLs. Results and conclusions: Compared to the limited number of novel commercially available AChEI analogs, many new natural compounds were patented for AD treatment. These might represent a starting point for the rational design of new MTDLs.     

Comparative studies using the Morris water maze to assess spatial memory deficits in two transgenic mouse models of Alzheimer's disease

Evaluation of the efficacy of novel therapeutics for potential treatment of Alzheimer's disease (AD) requires an animal model that develops age‐related cognitive deficits reproducibly between independent groups of investigators. Herein we assessed comparative temporal changes in spatial memory function in two commercially available transgenic mouse models of AD using the Morris water maze (MWM), incorporating both visible and hidden platform training. Individual cohorts of cDNA‐based ‘line 85’‐derived double‐transgenic mice coexpressing the ‘Swedish’ mutation of amyloid precursor protein (APPSwe) and the presenillin 1 (PS1) ‘dE9’ mutation were assessed in the MWM at mean ages of 3.6, 9.3 and 14.8 months. We found significant deficits in spatial memory retention in APPSwe/PS1dE9 mice aged 3.6 months and robust deficits in spatial memory acquisition and retention in APPSwe/PS1dE9 mice aged 9.3 months, with a further significant decline by age 14.8 months. β‐Amyloid deposits were present in brain sections by 7.25 months of age. In contrast, MWM studies with individual cohorts (aged 4–21 months) of single‐transgenic genomic‐based APPSwe mice expressing APPSwe on a yeast artificial chromosomal (YAC) construct showed no significant deficits in spatial memory acquisition until 21 months of age. There were no significant deficits in spatial memory retention up to 21 months of age and β‐amyloid deposits were not present in brain sections up to 24 months of age. These data, generated using comprehensive study designs, show that APPSwe/PS1dE9 but not APPSwe YAC mice appear to provide a suitably robust model of AD for efficacy assessment of novel AD treatments in development.     

Immunotherapy for Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia worldwide. In AD the normal soluble amyloid β (sAβ) peptide is converted into oligomeric/fibrillar Aβ. The oligomeric forms of Aβ are thought to be the most toxic, while fibrillar Aβ becomes deposited as amyloid plaques and congophilic angiopathy, which serve as neuropathological markers of the disease. In addition the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is a critical part of the pathology. Numerous therapeutic interventions are under investigation to prevent and treat AD. Among the more exciting and advanced of these approaches is vaccination. Active and passive Immunotherapy targeting only Aβ has been successful in many AD model animal trials; however, the more limited human data has shown much less benefit so far, with encephalitis occurring in a minority of patients treated with active immunization and vasogenic edema or amyloid-related imaging abnormalities (ARIA) being a complication in some passive immunization trials. Therapeutic intervention targeting only tau has been tested only in mouse models; and no approaches targeting both pathologies concurrently has been attempted, until very recently. The immune approaches tried so far were targeting a self-protein, albeit in an abnormal conformation; however, effective enhanced clearance of the disease associated conformer has to be balanced with the potential risk of stimulating excessive toxic inflammation. The design of future more effective immunomodulatory approaches will need to target all aspects of AD pathology, as well as specifically targeting pathological oligomeric conformers, without the use of any self-antigen.     

New pharmacological strategies for treatment of Alzheimer's disease: focus on disease modifying drugs

Current approved drug treatments for Alzheimer disease (AD) include cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the NMDA receptor antagonist memantine. These drugs provide symptomatic relief but poorly affect the progression of the disease. Drug discovery has been directed, in the last 10 years, to develop 'disease modifying drugs' hopefully able to counteract the progression of AD. Because in a chronic, slow progressing pathological process, such as AD, an early start of treatment enhances the chance of success, it is crucial to have biomarkers for early detection of AD-related brain dysfunction, usable before clinical onset. Reliable early biomarkers need therefore to be prospectively tested for predictive accuracy, with specific cut off values validated in clinical practice. Disease modifying drugs developed so far include drugs to reduce β amyloid (Aβ) production, drugs to prevent Aβ aggregation, drugs to promote Aβ clearance, drugs targeting tau phosphorylation and assembly and other approaches. Unfortunately none of these drugs has demonstrated efficacy in phase 3 studies. The failure of clinical trials with disease modifying drugs raises a number of questions, spanning from methodological flaws to fundamental understanding of AD pathophysiology and biology. Recently, new diagnostic criteria applicable to presymptomatic stages of AD have been published. These new criteria may impact on drug development, such that future trials on disease modifying drugs will include populations susceptible to AD, before clinical onset. Specific problems with completed trials and hopes with ongoing trials are discussed in this review.     

Non-mammalian animal models of Parkinson's disease for drug discovery

Importance of the field: Parkinson's disease (PD) is a prevalent neurodegenerative disease affecting millions of predominantly elderly individuals worldwide. Despite intensive efforts devoted to drug discovery, the disease remains incurable. Compounding this problem is the current lack of a truly representative mammalian model of PD. However, a number of non-mammalian models of PD have been created in recent years that hold tremendous promise to accelerate our understanding of the disease as well as to transform the drug discovery process.

Areas covered in this review: This review provides an overview of the various Caenorhabditis elegans and Drosophila genetic models of PD that have been generated to date and discusses the utility of these model systems in the identification of molecules of potential therapeutic value for the PD patient.

What the reader will gain: Readers will appreciate the strengths (and limitations) of C. elegans and Drosophila in modeling salient features of the disease as well as their usefulness in uncovering novel gene–gene interaction and pathways relevant to PD pathogenesis. Readers will also appreciate how technological advancements have allowed the direct evaluation of novel compounds in these living models of PD in a virtually high-throughput manner.

Take home message: Non-mammalian models of PD provide a valuable in vivo platform for drug screening. Unlike cell-based systems, these living models with an intact nervous system allow for a more meaningful evaluation of the neuroprotective properties of genetic and chemical modifiers to be conducted.     

Development of new Alzheimer's disease drug candidates using donepezil as a key model

Alzheimer's disease (AD) is one of the most prevalent geriatric diseases and a significant cause of high mortality. This crippling disorder is becoming more prevalent at an unprecedented rate, which has led to an increase in the financial cost of caring. It is a pathologically complicated, multifactorial disease characterized by β-amyloid precipitation, β-amyloid oligomer production, decrease in cholinergic function, and dysregulation of other neurotransmitter systems. Due to the pathogenic complexity of AD, multitarget drugs that can simultaneously alternate multiple biological targets may enhance the therapeutic efficacy. Donepezil (DNP) is the most potent approved drug for the treatment of AD. It has a remarkable effect on a number of AD-related processes, including cholinesterase activity, anti-Aβ aggregation, oxidative stress, and more. DNP resembles an excellent scaffold to be hybridized with other pharmacophoric moieties having biological activity against AD pathological factors. There have been significant attempts made to modify the structure of DNP to create new bioactive chemical entities with novel structural patterns. In this review, we highlight recent advances in the development of multiple-target DNP-hybridized models for the treatment of AD that can be used in the future in the rational design of new potential AD therapeutics. The design and development of new drug candidates for the treatment of AD using DNP as a molecular scaffold have also been reviewed and summarized.     

New and emerging treatments for Alzheimer's disease

Introduction: Alzheimer's disease and other dementias represent a significant and increasing clinical challenge. Dementia is also associated with a substantial economic cost and burden to health service provision. Existing treatments slow the progression of symptoms of the disease, but their efficacy does not extend to all patients and is not sustained beyond an average of 6 months. It is, therefore, critical to address the current lack of effective treatments to target the underlying pathology and disease process in Alzheimer's disease.

Areas covered: This review aims to highlight the main areas of new therapeutic development and discuss some of the main therapies currently being evaluated in clinical trials. Despite a number of promising rationales for therapeutic treatments in Alzheimer's disease, very few of these avenues have been developed beyond preclinical studies. The predominant focus of the current article is on treatments currently in Phase II and Phase III clinical trials, but some other promising areas of development are also discussed. There are currently only three therapeutics being investigated in Phase III clinical trials. This emphasizes the substantial caution and underinvestment in treatment development in this area.

Expert opinion: There is a distinct lack of novel approaches in the pipeline, and whether there is a new disease-modifying therapy for Alzheimer's disease in the next 5 years almost entirely depends on the success of currently ongoing immunotherapy studies. Importantly, there is potential benefit in exploring existing licensed treatments alongside novel drug development to increase the focus on novel targets within this time frame.     

白藜芦醇治疗阿尔茨海默病的研究进展

神经退行性疾病是一种慢性进展性疾病,其特点是中枢神经系统神经元的逐渐丧失。由于血脑屏障的存在,经典的抗炎药物如类固醇激素和非甾体类抗炎药,对神经系统疾病的治疗作用有限。因此,开发新的抗炎药物,对于预防和治疗神经系统疾病具有重要的意义。白藜芦醇是一种有很强活性的天然多酚类物质,目前研究已显示其具有心血管保护、神经保护、免疫调节、肿瘤的化学预防作用。近年来还发现其具有抗神经炎症作用,可用于治疗神经精神性疾病,如帕金森病、阿尔茨海默病(AD)和亨廷顿症等。综述白藜芦醇对AD的保护作用及其机制研究进展,为进一步推进白藜芦醇用于防治AD的研究提供参考。     

Mitochondrial abnormalities: A primary basis for oxidative damage in Alzheimer's disease

The most striking feature of Alzheimer's disease (AD) is the number of abnormalities affecting essentially every aspect of brain homeostasis. Recent work suggests that increased oxidative stress that damages lipids, proteins, and nucleic acids and results in the accumulation of redox‐active metals may be responsible for the diversity of systems involved. Interestingly, all of the genetic factors, β‐protein precursor, presenilins, and apolipoprotein E, have been linked to reactive oxygen species production or apoptosis, a process intimately associated with oxidative stress. This leaves open the question of why oxidative damage is increased in AD. In studies of mitochondria, we demonstrated increased mitochondrial DNA specifically in vulnerable neurons in cases of AD, suggesting that AD is marked by a fundamental abnormality in neuronal metabolism. Oxidative stress, therefore, seems to be the element linking the multitude of changes in Alzheimer's disease to a fundamental metabolic deficiency. Drug Dev. Res. 46:26–33, 1999. © 1999 Wiley‐Liss, Inc.     

Fruitful research: drug target discovery for neurodegenerative diseases in Drosophila

Introduction: Although vertebrate model systems have obvious advantages in the study of human disease, invertebrate organisms have contributed enormously to this field as well. The conservation of genome structure and physiology among organisms poses unexpected peculiarities, and the redundancy in certain gene families or the presence of polymorphisms that can slightly alter gene expression can, in certain instances, bring invertebrate systems, such as Drosophila, closer to humans than mice and vice versa. This necessitates the analysis of disease pathways in multiple model organisms.

Areas covered: The author highlights findings from Drosophila models of neurodegenerative diseases that have occurred in the past few years. She also highlights and discusses various molecular, genetic and genomic tools used in flies, as well as methods for generating disease models. Finally, the author describes Drosophila models of Alzheimer's, Parkinson's tri-nucleotide repeat diseases, and Fragile X syndrome and summarizes insights in disease mechanisms that have been discovered directly in fly models.

Expert opinion: Full genome genetic screens in Drosophila can lead to the rapid identification of drug target candidates that can be subsequently validated in a vertebrate system. In addition, the Drosophila models of neurodegeneration may often show disease phenotypes that are absent in equivalent mouse models. The author believes that the extensive contribution of Drosophila to both new disease drug target discovery, in addition to target validation, makes them indispensible to drug discovery and development.     

Safety and tolerability of transdermal and oral rivastigmine in Alzheimer's disease and Parkinson's disease dementia

Importance of the field: Cholinesterase inhibitors are the mainstay of symptomatic therapy for Alzheimer's disease (AD). Rivastigmine, an inhibitor of both acetylcholinesterase and butyrylcholinesterase, is available as a transdermal patch and in oral forms. It is also approved for the treatment of Parkinson's disease dementia (PDD) in many countries. The objective of this article is to review the safety and tolerability profile of transdermal and oral rivastigmine in AD and PDD patients.

Areas covered in this review: Articles were identified by searching MEDLINE in July 2009 using the terms rivastigmine, Exelon, ENA 713 and clinical trial. All double-blind, placebo-controlled randomized trials in which rivastigmine monotherapy was administered to AD or PDD patients for longer than 2 weeks were included.

What the reader will gain: This article provides a comprehensive summary of currently available safety data on rivastigmine.

Take home message: The main adverse events reported with rivastigmine therapy are gastrointestinal in nature. However, the transdermal patch appears to reduce these side effects, allowing more patients to access higher therapeutic doses. Overall, the safety profile of rivastigmine is favorable and the improved tolerability offered by the rivastigmine patch suggests that transdermal delivery may be the best way to deliver this drug in AD and PDD patients.