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Disease models: relevance is everything
Disease models
MOLECULAR MEDICINE TODAY, JUNE 1999 (VOL. 5)
Disease models: relevance is everything Welcome to a new addition to MMT Ð a section dedicated to modelling disease. Disease models are a vital tool for molecular medicine; we use them not only to gain insight into the molecular basis of disease, but also as pre-clinical screens to test the safety and efficacy of potential new therapies. For both applications, the relevance of the model is a key determinant of success and, in the past, too little importance has been placed on this. Many novel therapeutics have yielded disappointing results in clinical trials despite encouraging results at the pre-clinical testing stage; there are many reasons for such failures, but pre-clinical testing of new treatments in inappropriate models can be a significant and avoidable contributor. Knockout and transgenic technologies have made the creation of mouse models of monogenic disorders almost routine; Ôknocking inÕ specific mutations and conditionally knocking out genes in a tissue-specific and/or time-dependent
manner adds extra layers of sophistication that can answer increasingly specific questions about the molecular basis of disease, as well as solving important problems in fundamental biology. But more complex diseases present a more formidable challenge: it is difficult to produce a model that accurately reflects any disease for which the fundamental cause is poorly understood. Instead, we often have to rely on mimicking symptoms. For example, the hemiparkinsonian rat, a classical animal model of ParkinsonÕs disease (PD), is the result of acute chemical destruction of the neurons in the substantia nigra; although the result mimics advanced PD well enough, the cause and time-course bear little resemblance to the disease being modelled. Although models such as the hemiparkinsonian rat have served us well in the past, as therapies evolve from symptomatic treatment to causative treatment, so must our models.
The Disease models section is designed to do the assessment for you: each model is compared and contrasted with the human disease to ensure that the reader can decide how appropriate a certain model is for a particular application. We hope that Disease models will not only be of educational value but will also stimulate the use and development of models that are truly relevant to human disease, which will eventually catalyse the development of safe and efficacious therapeutics for human use. We are keen to hear your comments about the Disease models section, as well as suggestions for articles. Please e-mail comments and suggestions to: [email protected] Catherine Brooksbank Molecular Medicine Today
Animal models of AlzheimerÕs disease Linda Slanec Higgins
AlzheimerÕs disease (AD) is a progressive, neurodegenerative disorder and the most common dementia of aging. Clinically, AD is a syndrome that first presents with memory impairment, which is followed by increasing cognitive and, eventually, global deficits. Pathologically, AD is characterized by the presence of abundant neuritic plaques and neurofibrillary tangles (NFTs) and by synaptic and neuronal loss. Plaques are predominantly composed of fibrillar deposits of b-amyloid (Ab), a 39Ð43 amino-acid peptide derived from the bamyloid precursor protein (APP) and also contain a collection of immune, and other, proteins. NFTs are intraneuronal inclusions composed mostly of hyperphosphorylated tau, a microtubule-binding protein. The anatomical pattern of these pathological hallmarks is coincident with a profound and highly selective neurodegeneration that affects the neural substrates of memory and higher cognition. Reactive astrogliosis and microgliosis are prominent in affected areas but are absent from regions where diffuse Ab deposition has occurred in the absence of disease progression. The precise cellular and molecular mechanisms that underlie AD pathology remain unclear. 274
Although most cases of AD are sporadic, familial forms of the disease (FAD) have been extremely informative1. Multiple mutations in the genes that encode presenilins 1 and 2 (PS1 and PS2) and APP cause the autosomal dominant inheritance of early-onset AD, a form of AD that is almost fully penetrant. Inheritance of the e4 allele of apolipoprotein E (apoE) is a major risk factor that decreases the age of onset in a dose-dependent manner. Collectively, this genetic information has provided the basis for the generation of transgenic models of AD. By probing the effects of defined genetic alterations, it is possible to separate etiological factors from epiphenomena. Remarkable success has been attained in producing AD-like amyloid deposition in transgenic mice (Table 1). Animals that overexpress human FAD APP in neurons have been generated by several groups2,3. If APP expression exceeds endogenous levels by fivefold or more, significant Ab deposition is observed. The amyloid burden in brains of very old mice can even exceed that of an end-stage AD brain. The morphology of the diffuse deposits and mature plaques resembles that of AD brains (Fig. 1). Notably, the regional
distribution of deposition in the various APP transgenic pedigrees largely parallels that in the
Figure 1. Robust b-amyloid (Ab) deposition in the brain of an aged mouse that is transgenic for human familial AlzheimerÕs disease (FAD). b-amyloid precursor protein (APP) is revealed by immunoreactivity to the monoclonal antibody, mAb 4.1, which is specific for human Ab. This mouse, which is homozygous for PDAPP (Refs 2,3), expresses high levels of the transgene in neurons. The cortex, at the top, and the hippocampus, at the bottom, are separated by the fiber tracts of the corpus callosum.
1357-4310/99/$ - see front matter © 1999 Elsevier Science. All rights reserved.
MOLECULAR MEDICINE TODAY, JUNE 1999 (VOL. 5)
Disease models: relevance is everything Welcome to a new addition to MMT Ð a section dedicated to modelling disease. Disease models are a vital tool for molecular medicine; we use them not only to gain insight into the molecular basis of disease, but also as pre-clinical screens to test the safety and efficacy of potential new therapies. For both applications, the relevance of the model is a key determinant of success and, in the past, too little importance has been placed on this. Many novel therapeutics have yielded disappointing results in clinical trials despite encouraging results at the pre-clinical testing stage; there are many reasons for such failures, but pre-clinical testing of new treatments in inappropriate models can be a significant and avoidable contributor. Knockout and transgenic technologies have made the creation of mouse models of monogenic disorders almost routine; Ôknocking inÕ specific mutations and conditionally knocking out genes in a tissue-specific and/or time-dependent
manner adds extra layers of sophistication that can answer increasingly specific questions about the molecular basis of disease, as well as solving important problems in fundamental biology. But more complex diseases present a more formidable challenge: it is difficult to produce a model that accurately reflects any disease for which the fundamental cause is poorly understood. Instead, we often have to rely on mimicking symptoms. For example, the hemiparkinsonian rat, a classical animal model of ParkinsonÕs disease (PD), is the result of acute chemical destruction of the neurons in the substantia nigra; although the result mimics advanced PD well enough, the cause and time-course bear little resemblance to the disease being modelled. Although models such as the hemiparkinsonian rat have served us well in the past, as therapies evolve from symptomatic treatment to causative treatment, so must our models.
The Disease models section is designed to do the assessment for you: each model is compared and contrasted with the human disease to ensure that the reader can decide how appropriate a certain model is for a particular application. We hope that Disease models will not only be of educational value but will also stimulate the use and development of models that are truly relevant to human disease, which will eventually catalyse the development of safe and efficacious therapeutics for human use. We are keen to hear your comments about the Disease models section, as well as suggestions for articles. Please e-mail comments and suggestions to: [email protected] Catherine Brooksbank Molecular Medicine Today
Animal models of AlzheimerÕs disease Linda Slanec Higgins
AlzheimerÕs disease (AD) is a progressive, neurodegenerative disorder and the most common dementia of aging. Clinically, AD is a syndrome that first presents with memory impairment, which is followed by increasing cognitive and, eventually, global deficits. Pathologically, AD is characterized by the presence of abundant neuritic plaques and neurofibrillary tangles (NFTs) and by synaptic and neuronal loss. Plaques are predominantly composed of fibrillar deposits of b-amyloid (Ab), a 39Ð43 amino-acid peptide derived from the bamyloid precursor protein (APP) and also contain a collection of immune, and other, proteins. NFTs are intraneuronal inclusions composed mostly of hyperphosphorylated tau, a microtubule-binding protein. The anatomical pattern of these pathological hallmarks is coincident with a profound and highly selective neurodegeneration that affects the neural substrates of memory and higher cognition. Reactive astrogliosis and microgliosis are prominent in affected areas but are absent from regions where diffuse Ab deposition has occurred in the absence of disease progression. The precise cellular and molecular mechanisms that underlie AD pathology remain unclear. 274
Although most cases of AD are sporadic, familial forms of the disease (FAD) have been extremely informative1. Multiple mutations in the genes that encode presenilins 1 and 2 (PS1 and PS2) and APP cause the autosomal dominant inheritance of early-onset AD, a form of AD that is almost fully penetrant. Inheritance of the e4 allele of apolipoprotein E (apoE) is a major risk factor that decreases the age of onset in a dose-dependent manner. Collectively, this genetic information has provided the basis for the generation of transgenic models of AD. By probing the effects of defined genetic alterations, it is possible to separate etiological factors from epiphenomena. Remarkable success has been attained in producing AD-like amyloid deposition in transgenic mice (Table 1). Animals that overexpress human FAD APP in neurons have been generated by several groups2,3. If APP expression exceeds endogenous levels by fivefold or more, significant Ab deposition is observed. The amyloid burden in brains of very old mice can even exceed that of an end-stage AD brain. The morphology of the diffuse deposits and mature plaques resembles that of AD brains (Fig. 1). Notably, the regional
distribution of deposition in the various APP transgenic pedigrees largely parallels that in the
Figure 1. Robust b-amyloid (Ab) deposition in the brain of an aged mouse that is transgenic for human familial AlzheimerÕs disease (FAD). b-amyloid precursor protein (APP) is revealed by immunoreactivity to the monoclonal antibody, mAb 4.1, which is specific for human Ab. This mouse, which is homozygous for PDAPP (Refs 2,3), expresses high levels of the transgene in neurons. The cortex, at the top, and the hippocampus, at the bottom, are separated by the fiber tracts of the corpus callosum.
1357-4310/99/$ - see front matter © 1999 Elsevier Science. All rights reserved.