Editorial [Hot topic: Transgenic Animal Models of Neurodegenerative Diseases (Guest Editor: Stephen D. Skaper)]
Human neurodegenerative diseases are devastating illnesses that predominantly affect elderly people, and represent a tremendous unmet medical need. Consider, for example, Alzheimer's disease. Memory progressively fails, complex tasks become even more difficult, and oncefamiliar situations and people suddenly appear strange, even threatening. Over years, afflicted patients lose virtually all abilities and succumb to the disease. The majority of chronic neurodegenerative diseases are associated with the accumulation of misfolded proteins into aggregates that contain fibrillar structures, eventually causing the progressive loss of neurons in the brain and nervous system. Most of these proteinopathies are sporadic and the cause of pathogenesis remains elusive. Heritable forms are associated with genetic defects, suggesting that the affected protein is causally related to disease formation and/or progression. The limitations of human genetics, however, make it necessary to use model systems to analyse affected genes and pathways in more detail. Animal models have contributed considerably to advancing our understanding of the pathophysiological mechanisms underlying neurodegenerative disorders and have pointed to novel strategies for drug development. The successful use of animal models in drug discovery relies on both the development of valid disease models and the availability of adequate testing paradigms for evaluating the effects of different therapeutic approaches.
In the opening article, Wilcock provides an overview of AD, and mouse models used for its study. AD is a progressive, neurodegenerative disorder characterized pathologically by amyloid plaques composed of aggregated amyloid β-peptide (Aβ), neurofibrillary tangles composed of aggregated, hyperphosphorylated tau protein, and neuron loss. While the disease was first described in 1906, transgenic mouse models for the study of AD pathologies have only been available for fifteen years. Despite the generation of many different mouse models that develop amyloid plaques or neurofibrillary tangles, mouse models demonstrating the two pathologies together have only recently been made. Also, neuron loss has been difficult to achieve in many models. Most recently, several transgenic mice have been generated that do demonstrate all three pathological characteristics of AD; amyloid plaques, neurofibrillary tangles and neuron loss. This review discusses the advances made in our understanding of AD pathology using transgenic mouse models, and some of the limitations associated with studying these mice and how transgenic mouse models have contributed to the development of therapeutics for the treatment of AD.
A critical requirement in the development of AD therapeutics is a demonstration of the in vivo efficacy of compounds in pre-clinical disease relevant models. One of the most frequently used models in AD research are transgenic mice over-expressing mutant forms of human amyloid precursor protein (APP) that are associated with early-onset familial AD. Hussain carries on this theme by highlighting how APP transgenic mouse models have successfully been used in drug discovery to support the progression of Aβ lowering therapeutics to clinical trials to ultimately test the 'amyloid hypothesis' of AD. These mice exhibit an age-dependent accumulation and deposition of Aβ as extracellular plaques in the brain, and thereby depict one of the key pathologies observed in the brains of AD patients. Although these mouse models do not recapitulate all the pathological features of AD, they have been invaluable in the development of therapeutic agents aimed at lowering Aβ production, inhibiting Aβ deposition or facilitating Aβ clearance. Further development of these APP transgenic models led to the incorporation of transgenes for human mutant presenilins, resulting in an accelerated Aβ deposition rate and human mutant tau protein leading to neurofibrillary tangle-like pathology. The latter was a major advance in the development of AD models, as it allowed researchers to investigate the interplay between the two key pathologies of AD.
Tauopathies, including AD, are neurodegenerative diseases characterized by the deposition of hyperphosphorylated tau protein in the CNS, and are the major cause of dementia in later life. In their review, Noble, Hanger, and Gallo discuss the advances made in developing mouse models that recapitulate, to varying extents, the development of human tau pathology, and the learning and memory deficits characteristic of some tauopathies. Such models have been used to shown promising disease-modifying effects in pre-clinical testing of new therapeutics. Some of the most enlightening models developed to date either constitutively or inducibly express pathogenic tau mutations. These animals have been instrumental in defining critical disease-related mechanisms, including the observation that tangles are not the toxic form of tau in disease. The authors appraise the strengths and weaknesses of well characterised transgenic models that emulate human tauopathy, and then summarise the use of tau mice for the development and evaluation of new therapeutic approaches, and their utility in identifying novel drug targets. In addition, they review the parameters to be considered in the development of the next generation of mouse models of tauopathy, aimed at further increasing our understanding of disease aetiology and in evaluating novel treatments....
Document Type: Research Article
Department of Pharmacology and Anesthesiology University of Padova Largo “E. Meneghetti” 2 35131 Padova Italy.
Publication date: August 1, 2010
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CNS & Neurological Disorders - Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular targets involved in neurological and central nervous system (CNS) disorders e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will contain a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in neurological and CNS disorders. As the discovery, identification, characterization and validation of novel human drug targets for neurological and CNS drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.