Neurogenesis in mouse models of Alzheimer's disease

The brains of the adult mouse and human possess neural stem cells (NSCs) that retain the capacity to generate new neurons through the process of neurogenesis. They share the same anatomical locations of stem cell niches in the brain, as well as the prominent feature of rostral migratory stream formed by neuroblasts migrating from the lateral ventricles towards the olfactory bulb. Therefore the mouse possesses some fundamental features that may qualify it as a relevant model for adult human neurogenesis. Adult born young hippocampal neurons in the mouse display the unique property of enhanced plasticity, and can integrate physically and functionally into existing neural circuits in the brain. Such crucial properties of neurogenesis may at least partially underlie the improved learning and memory functions observed in the mouse when hippocampal neurogenesis is augmented, leading to the suggestion that neurogenesis induction may be a novel therapeutic approach for diseases with cognitive impairments such as Alzheimer's disease (AD). Research towards this goal has benefited significantly from the use of AD mouse models to facilitate the understanding in the impact of AD pathology on neurogenesis. The present article reviews the growing body of controversial data on altered neurogenesis in mouse models of AD and attempts to assess their relative relevance to humans.     

Motor impairment in Alzheimer's disease and transgenic Alzheimer's disease mouse models

In this commentary, we accent the accumulating evidence for motor impairment as a common feature of early Alzheimer's disease (AD) pathology. In addition, we summarize the state of knowledge on this phenotype in experimental mouse models, expressing AD-associated genes like tau or amyloid precursor protein.     

APP mouse models for Alzheimer's disease preclinical studies

Animal models of human diseases that accurately recapitulate clinical pathology are indispensable for understanding molecular mechanisms and advancing preclinical studies. The Alzheimer's disease (AD) research community has historically used first‐generation transgenic (Tg) mouse models that overexpress proteins linked to familial AD (FAD), mutant amyloid precursor protein (APP), or APP and presenilin (PS). These mice exhibit AD pathology, but the overexpression paradigm may cause additional phenotypes unrelated to AD. Second‐generation mouse models contain humanized sequences and clinical mutations in the endogenous mouse App gene. These mice show Aβ accumulation without phenotypes related to overexpression but are not yet a clinical recapitulation of human AD. In this review, we evaluate different APP mouse models of AD, and review recent studies using the second‐generation mice. We advise AD researchers to consider the comparative strengths and limitations of each model against the scientific and therapeutic goal of a prospective preclinical study.     

Transgenic models of Alzheimer's disease: Better utilization of existing models through viral transgenesis

Animal models have been used for decades in the Alzheimer's disease (AD) research field and have been crucial for the advancement of our understanding of the disease. Most models are based on familial AD mutations of genes involved in the amyloidogenic process, such as the amyloid precursor protein (APP) and presenilin 1 (PS1). Some models also incorporate mutations in tau (MAPT) known to cause frontotemporal dementia, a neurodegenerative disease that shares some elements of neuropathology with AD. While these models are complex, they fail to display pathology that perfectly recapitulates that of the human disease. Unfortunately, this level of pre-existing complexity creates a barrier to the further modification and improvement of these models. However, as the efficacy and safety of viral vectors improves, their use as an alternative to germline genetic modification is becoming a widely used research tool. In this review we discuss how this approach can be used to better utilize common mouse models in AD research. This article is part of a Special Issue entitled: Animal Models of Disease.     

Alzheimer's disease: Transgenic models to test new chemicals and pharmaceuticals

Alzheimer's disease is the most common form of senile dementia and is predicted to become even more prevalent as the proportion of elderly in the population increases over the next few decades. As yet, there are no effective treatments for the disorder. A major limitation to identifying new drugs and therapeutic targets for Alzheimer's disease has been the absence of an animal model displaying typical Alzheimer's pathology. Transgenic technology is now providing a powerful new approach for the development of animal models of Alzheimer's disease.     

Transgenic mouse models for ADHD

Attention-deficit hyperactivity disorder (ADHD) is a developmental disorder characterized by symptoms of inattention, impulsivity and hyperactivity that adversely affect many aspects of life. Whereas the etiology of ADHD remains unknown, growing evidence indicates a genetic involvement in the development of this disorder. The brain circuits associated with ADHD are rich in monoamines, which are involved in the mechanism of action of psychostimulants and other medications used to treat this disorder. Dopamine (DA) is believed to play a major role in ADHD but other neurotransmitters are certainly also involved. Genetically modified mice have become an indispensable tool used to analyze the contribution of genetic factors in the pathogenesis of human disorders. Although rodent models cannot fully recapitulate complex human psychiatric disorders such as ADHD, transgenic mice offer an opportunity to directly investigate in vivo the specific roles of novel candidate genes identified in ADHD patients. Several knock-out and transgenic mouse models have been proposed as ADHD models, mostly based on targeting genes involved in DA transmission, including the gene encoding the dopamine transporter (DAT1). These mutant models provided an opportunity to evaluate the contribution of dopamine-related processes to brain pathology, to dissect the neuronal circuitry and molecular mechanisms involved in the antihyperkinetic action of psychostimulants and to evaluate novel treatments for ADHD. New transgenic models mouse models targeting other genes have recently been proposed for ADHD. Here, we discuss the recent advances and pitfalls in modeling ADHD endophenotypes in genetically altered animals.     

Transgenic potato expressing Abeta reduce Abeta burden in Alzheimer's disease mouse model

Beta amyloid (Abeta) is believed one of the major pathogens of Alzheimer's disease (AD), and the reduction of Abeta is considered a primary therapeutic target. Immunization with Abeta can reduce Abeta burden and pathological features in transgenic AD model mice. Transgenic potato plants were made using genes encoding 5 tandem repeats of Abeta1-42 peptides with an ER retention signal. Amyloid precursor protein transgenic mice (Tg2576) fed with transgenic potato tubers with adjuvant showed a primary immune response and a partial reduction of Abeta burden in the brain. Thus, Abeta tandem repeats can be expressed in transgenic potato plants to form immunologically functional Abeta, and these potatoes has a potential to be used for the prevention and treatment of AD.     

Anti-amyloid activity of neprilysin in plaque-bearing mouse models of Alzheimer's disease

Abnormally high concentrations of beta-amyloid peptide (Abeta) and amyloid plaque formation in Alzheimer's disease (AD) may be caused either by increased generation or by decreased degradation of Abeta. Therefore, activation of mechanisms that lower brain Abeta levels is considered valuable for AD therapy. Neuronal upregulation of neprilysin (NEP) in young transgenic mice expressing the AD-causing amyloid precursor protein mutations (SwAPP) led to reduction of brain Abeta levels and delayed Abeta plaque deposition. In contrast, a comparable increase of brain NEP levels in aged SwAPP mice with pre-existing plaque pathology did not result in a significant reduction of plaque pathology. Therefore, we suggest that the potential of NEP for AD therapy is age-dependent and most effective early in the course of AD pathophysiology.     

Transgenic mouse models of amyotrophic lateral sclerosis

The discovery of missense mutations in the gene coding for the Cu/Zn superoxide dismutase 1 (SOD1) in subsets of familial cases was rapidly followed by the generation of transgenic mice expressing various forms of SOD1 mutants. The mice overexpressing high levels of mutant SOD1 mRNAs do develop motor neuron disease but unraveling the mechanisms of pathogenesis has been very challenging. Studies with mouse lines suggest that the toxicity of mutant SOD1 is unrelated to copper-mediated catalysis but rather to propensity of a subfraction of mutant SOD1 proteins to form misfolded protein species and aggregates. However, the mechanism of toxicity of SOD1 mutants remains to be elucidated. Involvement of cytoskeletal components in ALS pathogenesis is supported by several mouse models of motor neuron disease with neurofilament abnormalities and with genetic defects in microtubule-based transport. Here, we describe how transgenic mouse models have been used for understanding pathogenic pathways of motor neuron disease and for pre-clinical drug testing.     

Protective effects of positive lysosomal modulation in Alzheimer's disease transgenic mouse models

Alzheimer's disease (AD) is an age-related neurodegenerative pathology in which defects in proteolytic clearance of amyloid β peptide (Aβ) likely contribute to the progressive nature of the disorder. Lysosomal proteases of the cathepsin family exhibit up-regulation in response to accumulating proteins including Aβ(1-42). Here, the lysosomal modulator Z-Phe-Ala-diazomethylketone (PADK) was used to test whether proteolytic activity can be enhanced to reduce the accumulation events in AD mouse models expressing different levels of Aβ pathology. Systemic PADK injections in APP(SwInd) and APPswe/PS1ΔE9 mice caused 3- to 8-fold increases in cathepsin B protein levels and 3- to 10-fold increases in the enzyme's activity in lysosomal fractions, while neprilysin and insulin-degrading enzyme remained unchanged. Biochemical analyses indicated the modulation predominantly targeted the active mature forms of cathepsin B and markedly changed Rab proteins but not LAMP1, suggesting the involvement of enhanced trafficking. The modulated lysosomal system led to reductions in both Aβ immunostaining as well as Aβ(x-42) sandwich ELISA measures in APP(SwInd) mice of 10-11 months. More extensive Aβ deposition in 20-22-month APPswe/PS1ΔE9 mice was also reduced by PADK. Selective ELISAs found that a corresponding production of the less pathogenic Aβ(1-38) occurs as Aβ(1-42) levels decrease in the mouse models, indicating that PADK treatment leads to Aβ truncation. Associated with Aβ clearance was the elimination of behavioral and synaptic protein deficits evident in the two transgenic models. These findings indicate that pharmacologically-controlled lysosomal modulation reduces Aβ(1-42) accumulation, possibly through intracellular truncation that also influences extracellular deposition, and in turn offsets the defects in synaptic composition and cognitive functions. The selective modulation promotes clearance at different levels of Aβ pathology and provides proof-of-principle for small molecule therapeutic development for AD and possibly other protein accumulation disorders.     

Transgenic models of Huntington's disease.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion. A mouse model of this disease has been generated by the introduction of exon 1 of the human HD gene carrying highly expanded CAG repeats into the mouse germ line (R6 lines). Transgenic mice develop a progressive neurological phenotype with a movement disorder and weight loss similar to that in HD. We have previously identified neuronal inclusions in the brains of these mice that have subsequently been established as the pathological hallmark of polyglutamine disease. Inclusions are present before symptoms, which in turn occur long before any selective neuronal cell death can be identified. We have extended the search for inclusions to skeletal muscle, which, like brain, contains terminally differentiated cells. We have conducted an investigation into the skeletal muscle atrophy that occurs in the R6 lines, (i) to provide possible insights into the muscle bulk loss observed in HD patients, and (ii) to conduct a parallel analysis into the consequence of inclusion formation to that being performed in brain. The identification of inclusions in skeletal muscle might be additionally useful in monitoring the ability of drugs to prevent inclusion formation in vivo.     

Transgenic animal models of cardiovascular disease

Transgenic experimentation has become a crucial part of hypertension and atherosclerosis research, and is growing more important in several other areas of cardiovascular disease. It has recently made a particular contribution to understanding the role of the renin-angiotensin system in controlling hypertension. The study of blood pressure regulation, cardiac hypertrophy, atherogenesis and thrombosis are also benefiting from the transgenic approach.     

Transgenic mouse models for studying adult neurogenesis

The mammalian hippocampus shows a remarkable capacity for continued neurogenesis throughout life. Newborn neurons, generated by the radial neural stem cells (NSCs), are important for learning and memory as well as mood control. During aging, the number and responses of NSCs to neurogenic stimuli diminish, leading to decreased neurogenesis and age-associated cognitive decline and psychiatric disorders. Thus, adult hippocampal neurogenesis has garnered significant interest because targeting it could be a novel potential therapeutic strategy for these disorders. However, if we are to use neurogenesis to halt or reverse hippocampal-related pathology, we need to understand better the core molecular machinery that governs NSC and their progeny. In this review, we summarize a wide variety of mouse models used in adult neurogenesis field, present their advantages and disadvantages based on specificity and efficiency of labeling of different cell types, and review their contribution to our understanding of the biology and the heterogeneity of different cell types found in adult neurogenic niches.     

Transgenic models for cytokine-induced neurological disease

Considerable evidence supports the idea that cytokines are important mediators of pathophysiologic processes within the central nervous system (CNS). Numerous studies have documented the increased production of various cytokines in the human CNS in a variety of neurological and neuropsychiatric disorders. Deciphering cytokine actions in the intact CNS has important implications for our understanding of the pathogenesis and treatment of these disorders. One approach to address this problem that has been used widely employs transgenic mice with CNS-targeted production of different cytokines. Transgenic production of cytokines in the CNS of mice allows not only for the investigation of complex cellular responses at a localized level in the intact brain but also more closely recapitulates the expression of these mediators as found in disease states. As discussed in this review, the findings show that these transgenic animals exhibit wide-ranging structural and functional deficits that are linked to the development of distinct neuroinflammatory responses which are relatively specific for each cytokine. These cytokine-induced alterations often recapitulate those found in various human neurological disorders not only underscoring the relevance of these models but also reinforcing the clinicopathogenetic significance of cytokines in diseases of the CNS.     

Transgenic animals in inflammatory disease models

Inflammatory diseases affect a significant portion of the population worldwide and have been intensely studied for several decades. The advent of transgenic technology has allowed researchers to study individual gene contributions to the pathogenesis of these diseases. This has been done using standard inflammatory disease models in transgenic animals and by identifying novel models through the spontaneous generation of disease in the transgenic animal. Recent advances have been made in the understanding of rheumatoid arthritis, pulmonary inflammation, multiple sclerosis and inflammatory bowel disease through the use of transgenic animals in models of human inflammatory disease.     

Free radical-mediated damage to brain in Alzheimer's disease and its transgenic mouse models

Advances in our understanding of the etiologies and pathogenesis of Alzheimer's disease (AD) highlight a role for free radical-mediated injury to brain regions from early stages of this illness. Here we will review the evidence from transgenic mouse models of AD, autopsy samples, and human biofluids obtained during life paying particular attention to the stage of disease. In addition, we will review the epidemiologic literature that addresses the potential of anti-oxidants to prevent incident dementia from AD, and the clinical trial literature that addresses anti-oxidant preventative or therapeutic strategies for different stage of AD. Future efforts in preclinical models and ultimately clinical trials are needed to define optimally effective agents and combinations, doses, and timing to suppress safely this facet of AD.     

Ultrasound enhanced delivery of molecular imaging and therapeutic agents in Alzheimer's disease mouse models

Alzheimer's disease is a neurodegenerative disorder typified by the accumulation of a small protein, beta-amyloid, which aggregates and is the primary component of amyloid plaques. Many new therapeutic and diagnostic agents for reducing amyloid plaques have limited efficacy in vivo because of poor transport across the blood-brain barrier. Here we demonstrate that low-intensity focused ultrasound with a microbubble contrast agent may be used to transiently disrupt the blood-brain barrier, allowing non-invasive, localized delivery of imaging fluorophores and immunotherapeutics directly to amyloid plaques. We administered intravenous Trypan blue, an amyloid staining red fluorophore, and anti-amyloid antibodies, concurrently with focused ultrasound therapy in plaque-bearing, transgenic mouse models of Alzheimer's disease with amyloid pathology. MRI guidance permitted selective treatment and monitoring of plaque-heavy anatomical regions, such as the hippocampus. Treated brain regions exhibited 16.5+/-5.4-fold increase in Trypan blue fluorescence and 2.7+/-1.2-fold increase in anti-amyloid antibodies that localized to amyloid plaques. Ultrasound-enhanced delivery was consistently reproduced in two different transgenic strains (APPswe:PSEN1dE9, PDAPP), across a large age range (9-26 months), with and without MR guidance, and with little or no tissue damage. Ultrasound-mediated, transient blood-brain barrier disruption allows the delivery of both therapeutic and molecular imaging agents in Alzheimer's mouse models, which should aid pre-clinical drug screening and imaging probe development. Furthermore, this technique may be used to deliver a wide variety of small and large molecules to the brain for imaging and therapy in other neurodegenerative diseases.     

Genes, models and Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disorder that is claiming an increasing number of victims as the world population ages. The identification of gene mutations and polymorphisms that either cause AD or significantly increase the risk for developing it enabled the creation of a whole generation of realistic rodent models of the disease. Animals expressing mutated human amyloid precursor protein and presenilin 1 show dramatic parallels to AD, although none of the models appear to capture the full range of pathologies that characterize the human disease. Increased refinement of these models will enhance the already tantalizing possibility of treatment.     

Transgenic mouse models for the prevention of breast cancer

Breast cancer prevention research has made remarkable progress in the past decade. Much of this progress has come from clinical trials. However, in the future to test the many promising agents that are now available, pre-clinical models of breast cancer are needed. Such models are now available. Useful models include rat and mouse models, particularly, the genetically engineered mice (GEM). Many transgenic mouse models have been generated by manipulating growth factors and their receptors, cell cycle regulators, signal transduction pathways, cellular differentiation, oncogenes and tumor suppressor genes. The transgenes are induced to express in the mouse mammary glands under the control of various transgenic promoters, which have respective characteristics in expression pattern and other biological attributes. These models are providing invaluable insight on the molecular mechanisms of breast tumorigenesis. In this review, we discuss the relative relevance of the most commonly used transgenic mouse models for breast cancer prevention studies, and provide examples of how these transgenic models can be used to conduct cancer prevention research. Due to the multi-factor, multi-step nature of breast cancer, many factors should be incorporated into a valid prevention study. However, many barriers to progress must be overcome, including access to and availability of new cancer preventive drugs, and difficulties in conducting studies of combinations of preventive agents.