Volume 15, Number 4, December 2008 - Special Issue "Animal Models of Alzheimer’s Disease: Therapeutic Implications" (Guest Editor: Diana Woodruff-Pak)

Pages 507-521
Diana S. Woodruff-Pak
Animal Models of Alzheimer’s Disease: Therapeutic Implications
Abstract; This Special Issue of the Journal of Alzheimer’s Disease (JAD) provides an overview of animal models of Alzheimer’s disease (AD). Very few species spontaneously develop the cognitive, behavioral, and neuropathological symptoms of AD, yet AD research must progress at a more rapid pace than the rate of human aging. In recent years, a variety of models have been created – from tiny invertebrates with life spans measurable in months to huge mammals that live several decades. The fruit fly, Drosophila melanogaster, is a powerful genetic tool that has recently emerged as a model of AD with neural features and assessable learning and memory. Transgenic mice are the most widely used animal models of AD and have yielded significant research breakthroughs. Accelerated aging seen in the SAMP8 mouse is a non-transgenic model with great utility. Rat models provided early evidence about the deleterious impact of amyloid-β (Aβ) on neurons and continue to provide insights. Rabbits, as langomorphs, are more closely related to primates than are rodents and have conserved the sequence of Aβ in humans (as have canines and non-human primates). The hypercholesterolemic rabbit is an excellent AD model. The aging canine develops AD neuropathology spontaneously and is especially suitable for tests of therapeutics. Non-human primates are invaluable for the development of therapeutics translating to humans. Each animal model has limitations and strengths, but used together in complimentary fashion, animal models for research on AD are essential for rapid progress toward a cure.

Pages 523-540
Koichi Iijima, Kanae Iijima-Ando
Drosophila Models of Alzheimer’s Amyloidosis: The Challenge of Dissecting the Complex Mechanisms of Toxicity of Amyloid-β 42
Abstract: Alzheimer’s disease (AD) is the most common form of senile dementia, and a cure is desperately needed. The amyloid-β 42 (Aβ42) has been suggested to play a central role in the pathogenesis of AD. However, the mechanism by which Aβ42 causes AD remains unclear. To understand the pathogenesis and to develop therapeutic avenues, it is crucial to generate animal models of AD in genetically tractable organisms. Drosophila is a well-established model system for which abundant genetic tools are available. Moreover, its well organized brain permits the study of complex behaviors such as learning and memory. We have established transgenic flies that express human Aβ42 in the nervous system. These flies developed age-dependent short-term memory impairment and neurodegeneration. In this review, we will first describe transgenic Aβ42 fly models and discuss the unique features of this system compared to mouse AD models. Secondly, we will discuss the usage of the fly models to evaluate currently proposed therapeutic strategies. Thirdly, we will briefly review the results of a genetic screen for modifiers of Aβ42 toxicity in the fly model. Finally, we will discuss how to dissect the complex mechanisms of Aβ42 toxicity focusing on its aggregation propensity using the fly model system.

Pages 541-553
Vikram Khurana
Modeling Tauopathy in the Fruit Fly Drosophila melanogaster
Abstract: The fruit fly Drosophila melanogaster has emerged as a powerful system in which to model human disease. This review focuses on the utility of the fly to model tau-dependent neurodegeneration, a hallmark of Alzheimer’s disease and related neurodegenerative disorders. I provide a detailed description of fly tauopathy modelsand summarize a number of studies that demonstrate their ability to recapitulate both primary features of tauopathy, including tau-induced neurodegeneration and phosphorylation, and secondary features, including oxidative stress, cell-cycle activation and changes in the actin cytoskeleton. Important genetic and biochemical insights are discussed, and future directions proposed.

Pages 555-569
Donna M. Wilcock and Carol A. Colton
Anti-Amyloid-β Immunotherapy in Alzheimer’s Disease: Relevance of Transgenic Mouse Studies to Clinical Trials
Abstract: Therapeutic approaches to the treatment of Alzheimer’s disease are focused primarily on the amyloid-β peptide which aggregates to form amyloid deposits in the brain. The amyloid hypothesis states that amyloid is the precipitating factor that results in the other pathologies of Alzheimer’s disease. One such therapy that has attracted significant attention is anti-amyloid-β immunotherapy. First described in 1999, immunotherapy uses anti-amyloid-β antibodies to lower brain amyloid levels. Active and passive immunization were shown to lower brain amyloid levels and improve cognition in multiple transgenic mouse models. Mechanisms of action were studied in these mice and revealed a complex set of mechanisms that depended on the type of antibody used. When active immunization advanced to clinical trials a subset of patients developed meningoencephalitis, an event not predicted in mouse studies. It was suspected that a T-cell response due to the type of adjuvant used was the cause. Passive immunization has also advanced to Phase III clinical trials on the basis of successful transgenic mouse studies. Reports from the active immunization clinical trial indicated that, similarly to effects observed in mouse studies, amyloid levels in brain were reduced.

Pages 571-587
Carol A. Colton, Donna M. Wilcock, David A. Wink, Judianne Davis, William E. Van Nostrand, Michael P. Vitek
The Effects of NOS2 Gene Deletion on Mice Expressing Mutated Human AβPP
Abstract: Nitric oxide synthase 2 (NOS2) and its gene product, inducible NOS (iNOS) play an important role in neuroinflammation by generating nitric oxide (NO), a critical signaling and redox factor in the brain. Although NO is associated with tissue damage, it can also promote cell survival. We hypothesize that during long-term exposure to amyloid-β (Aβ) in Alzheimer’s disease (AD), NO levels fall in the brain to a threshold at which the protective effects of NO cannot be sustained, promoting Aβ mediated damage. Two new mouse models of AD have been developed that utilize this concept of NO’s action. These mice express human amyloid-β protein precursor (AβPP) mutations that generate Aβ peptides on a mouse NOS2 knockout background. The APP/NOS2-/- bigenic mice progress from Aβ production and amyloid deposition to hyperphosphorylated normal mouse tau at AD-associated epitopes, aggregation and redistribution of tau to somatodendritic regions of neurons and significant neuronal loss including loss of interneurons. This AD-like pathology is accompanied by robust behavioral changes. As APP/NOS2-/- bigenic mice more fully model the human AD disease pathology, they may serve as a tool to better understand disease progression in AD and the role of NO in altering chronic neurological disease processes.

Pages 589-603
Michael R. Foy, Michel Baudry, Roberta Diaz Brinton, Richard F. Thompson
Estrogen and Hippocampal Plasticity in Rodent Models
Abstract: Accumulating evidence indicates that ovarian hormones regulate a wide variety of non-reproductive functions in the central nervous system by interacting with several molecular and cellular processes. A growing animal literature using both adult and aged rodent models indicates that 17b-estradiol, the most potent of the biologically relevant estrogens, facilitates some forms of learning and memory, in particular those that involve hippocampal-dependent tasks. A recently developed triple-transgenic mouse (3xTg-AD) has been widely used as an animal model of Alzheimer’s disease, as this mouse exhibits an age-related and progressive neuropathological phenotype that includes both plaque and tangle pathology mainly restricted to hippocampus, amygdala and cerebral cortex. In this report, we examine recent studies that compare the effects of ovarian hormones on synaptic transmission and synaptic plasticity in adult and aged rodents. A better understanding of the non-reproductive functions of ovarian hormones has far-reaching implications for hormone therapy to maintain health and function within the nervous system throughout aging.

Pages 605-614
Dave Morgan, Sanjay Munireddy, Jennifer Alamed, Jason DeLeon, David M. Diamond, Paula Bickford, Michael Hutton, Jada Lewis, Eileen McGowan, Marcia N. Gordon
Apparent Behavioral Benefits of Tau Overexpression in P301L Tau Transgenic Mice
Abstract: Transgenic mice expressing human tau containing the P301L tau mutation (JNPL3; tau mice) develop motor neuron loss, paralysis and death between 7 and 12 months. Surprisingly, at 5 and 7 months of age, tau transgenic mice were superior to other genotypes in the rotarod task, and had near perfect scores on the balance beam and coat hanger tests. One tau transgenic mouse was performing at a superior level in the rotarod one day prior to developing paralysis. Cognitive function was also normal in the tau mice evaluated in the radial arm water maze and the Y-maze tasks. We also crossed the tau transgenic mice with Tg2576 amyloid-β protein precursor (AβPP) transgenic mice. Although AβPP mice were deficient in the radial arm maze task, AβPP+tau mice were not impaired, implying a benefit of the tau transgene. Some mice were homozygous for the retinal degeneration mutation (rd/rd) and excluded from the genotype analysis. Only the water maze task discriminated the rd/rd mice from nontransgenic mice. In conclusion, it seems that the modest tau overexpression or the presence of mutant tau in the JNPL3 tau mice may provide some benefit with respect to motor and cognitive performance before the onset of paralysis.

Pages 615-624
Merce Pallas, Antoni Camins, Mark A. Smith, George Perry, Hyoung-gon Lee, Gemma Casadesus
From Aging to Alzheimer’s Disease: Unveiling “The Switch” with the Senescence-Accelerated Mouse Model (SAMP8)
Abstract: Current mouse models of Alzheimer’s disease (AD) are restricted to the expression of AD-related pathology associated with specific mutations present in early-onset familial AD and thus represent <5% of AD cases. To date there are no mouse lines that model late-onset/age-related AD, the feature which accounts for the vast majority of cases. As such, based on current mutation-associated models, the chronology of events that lead to the disease in the aged population is difficult to establish. However, published data show that senescence-accelerated mouse (SAMP8), as a model of aging, display many features that are known to occur early in the pathogenesis of AD such as increased oxidative stress, amyloid-β alterations, and tau phosphorylation. Therefore, SAMP8 mice may be an excellent model for studying the earliest neurodegenerative changes associated with AD and provide a more encompassing picture of human disease, a syndrome triggered by a combination of age-related events. Here, the neurochemical, neuropathological, and behavioral alterations, characterized in SAMP8 mice are critically reviewed and discussed in relation to the potential use of this mouse model in the study of AD pathogenesis.

Pages 625-640
Aynun N. Begum, Fusheng Yang, Edmond Teng, Shuxin Hu, Mychica R. Jones, Emily R. Rosario, Walter Beech, Beverly Hudspeth, Oliver J. Ubeda, Greg M. Cole, Sally A. Frautschy
Use of Copper and Insulin-Resistance to Accelerate Cognitive Deficits and Synaptic Protein Loss in a Rat Aβ-Infusion Alzheimer’s Disease Model
Abstract: The rat amyloid-β (Aβ) intracerebroventricular infusion can model aspects of Alzheimer's disease (AD) and has predicted efficacy of therapies such as ibuprofen and curcumin in transgenic mouse models. High density lipoprotein (HDL), a normal plasma carrier of Ab, is used to attenuate Aβ aggregation within the pump, causing Aβ-dependent toxicity and cognitive deficits within 3 months. Our goal was to identify factors that might accelerate onset of Ab-dependent deficits to improve efficiency and cost-effectiveness of model. We focused on: 1) optimizing HDL-Aβ preparation for maximal toxicity; 2) evaluating the role of copper, a factor typically in water that can impact oligomer stability; and 3) determining impact of insulin resistance (type II diabetes), a risk factor for AD. In vitro studies were performed to determine doses of copper and methods of Aβ-HDL preparation that maximized toxicity. These preparations when infused resulted in earlier onset of cognitive deficits within 6 weeks post-infusion. Induction of insulin resistance did not exacerbate Aβ-dependent cognitive deficits, but did exacerbate synaptic protein loss. In summary, the newly described in vivo infusion model may be useful cost-effective method for screening for new therapeutic drugs for AD.

Pages 641-656
D. Larry Sparks
The Early and Ongoing Experience with the Cholesterol-Fed Rabbit as a Model of Alzheimer’s Disease: The Old, the New and the Pilot
Abstract: Pioneering autopsy studies revealed a possible link between coronary artery disease, cholesterol and Alzheimer’s disease (AD). In the cholesterol-fed rabbit model of human coronary artery disease, we identified numerous neuropathologic features of AD including central accumulation of amyloid-β (Aβ) and cognitive deficits compared to rabbits fed unaltered diet. Removing cholesterol from the diet or treatment with cholesterol-lowering medications reversed the severity of AD-like alterations. This fostered the rationale for testing a cholesterol-lowering statin medication for benefit in the treatment of AD. Further studies suggested that the cholesterol-fed rabbit was a viable model for AD, but the severity of the neuropathology produced exhibited gender-related differences. Furthermore the induction of AD-like neuropathology by dietary cholesterol was found to depend on the quality of water the animal was drinking. Cholesterol-fed rabbits drinking distilled water showed minimal central changes, whereas animals drinking distilled water supplemented with low levels of copper were severely affected. It was clear that cholesterol caused the over-production of Aβ in the brain and copper influenced its clearance to the blood. Emerging data suggest that low-density lipoprotein receptor-related protein-1 (LRP) on brain capillaries clears Aβ from brain and that excess circulating copper negatively influences this process.

Pages 657-671
Richard Coico, Diana Woodruff-Pak
Immunotherapy for Alzheimer’s Disease: Harnessing our Knowledge of T Cell Biology Using a Cholesterol-Fed Rabbit Model
Abstract: This timely special issue of the Journal of Alzheimer’s Disease provides the opportunity to examine interfaces between basic science and clinical medicine using animal models to develop more effective therapies for the treatment and, ideally, prevention of Alzheimer’s disease (AD). That some patients with AD enrolled in a clinical trial to inoculate against amyloid-β (Aβ) experienced a misdirected polarization of Th cells reminds us that our knowledge of T cell biology, immune regulation, and the precise functional properties of adjuvants is incomplete. We review this knowledge and consider the advantages of the rabbit for immunological studies. The langomorph species is proximate to primates on the phylogenetic scale, its amino acid sequence of Aβ is 97% identical to the human Aβ sequence, and the rabbit model system is extensively characterized on a form of associative learning with parallels in normal aging in rabbits and humans that is severely impaired in human AD. Cholesterol-fed rabbits treated with Aβ immunotherapy generate high titer anti-Aβ responses. The cholesterol-fed rabbit model of AD with its close parallels to human genetics and physiology, along with its validity from molecular to cognitive levels as a model of human AD, provides a promising vehicle for development of immunotherapies.

Pages 673-684
Othman Ghribi
Potential Mechanisms Linking Cholesterol to Alzheimer’s Disease-like Pathology in Rabbit Brain, Hippocampal Organotypic Slices, and Skeletal Muscle
Abstract: Epidemiological, animal, and cellular studies suggest that abnormalities in cholesterol metabolism are important in the pathogenesis of Alzheimer’s disease (AD), potentially by increasing amyloid-β (Aβ) peptide levels. Accumulation of Aβ in the brain is suggested to play a key role in the neurodegenerative processes by triggering the hyperphosphorylation of tau and the neuronal death that develop in the course of AD. However, the mechanisms by which cholesterol increases Aβ levels are still ill-defined. Previous and ongoing work from our laboratory indicates that hypercholesterolemia leads to the increased neuronal content of cholesterol and increased levels and processing of the amyloid-β protein precursor (AβPP). We also have found that the oxidized cholesterol metabolite, 27-hydroxycholestrol, increases Aβ levels in both organotypic hippocampal slices and in neuronal preparations cultured from adult rabbits. This cholesterol metabolite is predominantly formed in the circulation and, in contrast to cholesterol, has the ability to cross into the brain. These results may indicate that 27-hydroxycholestrol is the link between circulating cholesterol and AD-like pathology in the brain. We also have found pathological hallmarks in the skeletal muscle of cholesterol-fed rabbits that are suggestive of inclusion body myositis, a disease that shares some pathological similarities with AD.

Pages 685-707
Carl W. Cotman, Elizabeth Head
The Canine (Dog) Model of Human Aging and Disease: Dietary, Environmental and Immunotherapy Approaches
Abstract: Aged dogs (beagles) develop losses in executive function, learning and memory. The severity of decline in these cognitive domains represents a spectrum that captures normal aging, mild cognitive impairment and early/mild Alzheimer’s disease (AD) in humans. In parallel, dogs naturally accumulate several types of neuropathology (although not all) consistent with human brain aging and AD including cortical atrophy, neuron loss, loss of neurogenesis, amyloid-β (Aβ) plaques, cerebral amyloid angiopathy and oxidative damage. Many of these neuropathological features correlate with the extent of cognitive decline in a brain region-dependent manner. Dogs are ideally suited for longitudinal studies, and we provide a summary of the beneficial effects of an antioxidant diet, behavioral enrichment, and Aβ immunotherapy. In addition, combinatorial treatment approaches can be a powerful strategy for improving brain function through enhancement of multiple molecular pathways.

Pages 709-720
Jerry J. Buccafusco
Estimation of Working Memory in Macaques for Studying Drugs for the Treatment of Cognitive Disorders
Abstract: Non-human primates have served as subjects for studies of the cognition-enhancing potential of novel pharmacological agents for over 25 years. Only recently has a greater appreciation of the translational applicability of this model been realized. Though most Old-World monkeys do not appear to acquire an Alzheimer’s-like syndrome in old age, their value resides in the brain physiology they have in common with humans. Paradigms like the delayed matching-to-sample task engender behavior that models aspects of working memory that are substrates for the actions of cognition-enhancing drugs. Our studies have provided information relevant to factors that limit the effectiveness of clinical trial design for compounds that potentially improve cognition. For example, cognition-enhancing compounds from different pharmacological classes, when administered to monkeys, can exhibit remarkable pharmacodynamic effects that outlast the presence of the drug in the body. Studies with non-human primates also can provide information regarding dose ranges and individual subject sensitivity experienced in the clinic. Components of working memory are differentially sensitive to drug effects and may be characterized by different dose ranges for certain compounds, even within the same task. Examples are provided that underscore the possible idiosyncrasies of drug action in the pharmacology of cognition –which could be of critical importance in the design of clinical trials.