Functions of the APP gene family in the nervous system: insights from mouse models

The amyloid precursor protein (APP) plays a key role in the pathogenesis of Alzheimer's disease (AD), as proteolytical cleavage of APP gives rise to the β-amyloid peptide which is deposited in the brains of Alzheimer patients. During the past years, intense research efforts have been directed at elucidating the physiological function(s) of APP and the question of whether a perturbation of these functions contributes to AD pathogenesis. Indeed, a growing body of evidence has accumulated supporting a role of APP and the two closely related homologues APLP1 and APLP2 in various aspects of nervous system development and function, in particular, for synapse formation and function. This review summarizes recent insights into the in vivo role of the APP gene family from mice lacking individual or combinations of APP family members, with particular emphasis on recently generated knockin mice to examine the in vivo relevance of distinct functional domains.     

Natural killer cell differentiation: insights from knockout and transgenic mouse models and in vitro systems

Summary: In the last few years, the routine development of knockout and transgenic mice and the ease with which rare progenitor populations can be isolated from hematopoietic organs and cultured in vitro has facilitated significant advances in understanding the lineage and development of natural killer (NK) cells. Fluorescence-activated cell sorter analyses have identified a common lymphoid progenitor capable of giving rise to NK, T, and B cells, confirming the lymphoid origin of NK cells. Knockout and transgenic mouse models have pointed to an absolutely critical role for signals sent through the interleukin (IL)-2/lS receptor β (CD 122) chain and common γ (γc) chain for NK development. Such signals are likely relayed inside the cell by the tyrosine kinase Jak3, which associates with γc. Recently developed IL-15 and IL-15 receptor a knockout mice have pinpointed IL-15 as the mediator of this signal. Other mouse models have indicated an unexpected role for flt3 ligand in early NK-cell development as well as minor roles for stem cell factor and IL-7 in expanding NK-cell progenitor numbers. Finally, in vitro culture systems have proven useful in identifying the point in NK development at which each of these signals is critical.     

Dendritic vulnerability in neurodegenerative disease: insights from analyses of cortical pyramidal neurons in transgenic mouse models

In neurodegenerative disorders, such as Alzheimer’s disease, neuronal dendrites and dendritic spines undergo significant pathological changes. Because of the determinant role of these highly dynamic structures in signaling by individual neurons and ultimately in the functionality of neuronal networks that mediate cognitive functions, a detailed understanding of these changes is of paramount importance. Mutant murine models, such as the Tg2576 APP mutant mouse and the rTg4510 tau mutant mouse have been developed to provide insight into pathogenesis involving the abnormal production and aggregation of amyloid and tau proteins, because of the key role that these proteins play in neurodegenerative disease. This review showcases the multidimensional approach taken by our collaborative group to increase understanding of pathological mechanisms in neurodegenerative disease using these mouse models. This approach includes analyses of empirical 3D morphological and electrophysiological data acquired from frontal cortical pyramidal neurons using confocal laser scanning microscopy and whole-cell patch-clamp recording techniques, combined with computational modeling methodologies. These collaborative studies are designed to shed insight on the repercussions of dystrophic changes in neocortical neurons, define the cellular phenotype of differential neuronal vulnerability in relevant models of neurodegenerative disease, and provide a basis upon which to develop meaningful therapeutic strategies aimed at preventing, reversing, or compensating for neurodegenerative changes in dementia.     

Anaphylaxis: lessons from mouse models

Studies with mouse models demonstrate 2 pathways of systemic anaphylaxis: a classic pathway mediated by IgE, FcepsilonRI, mast cells, histamine, and platelet-activating factor (PAF) and an alternative pathway mediated by IgG, FcgammaRIII, macrophages, and PAF. The former pathway requires much less antigen and antibody than the latter. This is modified, however, by IgG antibodies that prevent IgE-mediated anaphylaxis by intercepting antigen before it binds to mast cell-associated IgE. Consequently, IgG antibodies block systemic anaphylaxis induced by small quantities of antigen but mediate systemic anaphylaxis induced by larger quantities. The importance of the alternative pathway in human subjects is unknown, but human IgG, IgG receptors, macrophages, mediators, and mediator receptors have appropriate properties to support this pathway if sufficient IgG and antigen are present. The severity of systemic anaphylaxis is increased by nitric oxide produced by the enzyme endothelial nitric oxide synthase and by the cytokines IL-4 and IL-13 and decreased by endogenous beta-adrenergic stimulation and receptors that contain ITIM that bind tyrosine phosphatases. Anaphylaxis is also suppressed by other receptors and ion channels that function through distinct mechanisms. Unlike systemic anaphylaxis, intestinal anaphylaxis (allergic diarrhea) is almost totally IgE and mast cell dependent and is mediated predominantly by PAF and serotonin. Some potent food allergens, including peanuts and tree nuts, can directly enhance anaphylaxis by stimulating an anaphylactoid response through the innate immune system. Results of these studies suggest novel prophylactic agents, including nonstimulatory anti-IgE mAbs, IL-4 receptor antagonists, PAF antagonists, and agents that cross-link FcepsilonRI or FcgammaRIII to an ITIM-containing inhibitory receptor.     

Poxvirus immune modulators: functional insights from animal models

Poxviruses express several different classes of immune modulators that suppress the host response to infection, including soluble cytokine binding proteins, serpins, chemokine binding proteins, a complement control protein, and members of the semaphorin and Toll/IL-1 receptor families. Biochemical activity of these proteins has been demonstrated by many in vitro studies. Conservation in evolution of poxvirus immune modulators implies that these genes are functional in vivo, but the results of infecting animals with knockout viruses have not always been clear cut. Studies involving different animal models are reviewed, and the criteria for suitable models are discussed. Challenges include finding an appropriate animal host, and using an inoculation route that resembles the process of natural infection. The fact that multiple immune modulators can target the same pathway at different steps may explain why single knockout mutants are not always attenuated in animals.     

The mechanisms of coronary restenosis: insights from experimental models

Since its introduction into clinical practice, more than 20 years ago, percutaneous transluminal coronary angioplasty (PTCA) has proven to be an effective, minimally invasive alternative to coronary artery bypass grafting (CABG). During this time there have been great improvements in the design of balloon catheters, operative procedures and adjuvant drug therapy, and this has resulted in low rates of primary failure and short-term complications. However, the potential benefits of angioplasty are diminished by the high rate of recurrent disease. Up to 40% of patients undergoing angioplasty develop clinically significant restenosis within a year of the procedure. Although the deployment of endovascular stents at the time of angioplasty improves the short-term outcome, 'in-stent' stenosis remains an enduring problem. In order to gain an insight into the mechanisms of restenosis, several experimental models of angioplasty have been developed. These have been used together with the tools provided by recent advances in molecular biology and catheter design to investigate restenosis in detail. It is now possible to deliver highly specific molecular antagonists, such as antisense gene sequences, to the site of injury. The knowledge provided by these studies may ultimately lead to novel forms of intervention. The present review is a synopsis of our current understanding of the pathological mechanisms of restenosis.     

Cells and cytokines in the pathogenesis of inflammatory bowel disease: new insights from mouse T cell transfer models

Recently, a number of experimental models of human inflammatory bowel disease (IBD) of immunological basis have been developed. These have proven useful tools in the study of IBD, allowing a more detailed dissection of the pathogenesis of the disease. Studies from these models have revealed new, important knowledge about environmental factors, cell subset, cytokines and effector molecules in the pathogenesis of IBD. This review focuses on recent advances in the understanding of the development of IBD obtained from adoptive CD4+ T cell transfer models of the disease.     

The many flavors of hyperhomocyst(e)inemia: insights from transgenic and inhibitor-based mouse models of disrupted one-carbon metabolism

Mouse models that perturb homocysteine metabolism, including genetic mouse models that result in deficiencies of methylenetetrahydrofolate reductase, methionine synthase, methionine synthase reductase, and cystathionine beta-synthase, and a pharmaceutically induced mouse model with a transient deficiency in betainehomocysteine methyl transferase, have now been characterized and can be compared. Although each of these enzyme deficiencies is associated with moderate to severe hyperhomocyst(e)inemia, the broader metabolic profiles are profoundly different. In particular, the various models differ in the degree to which tissue ratios of S-adenosylmethionine to S-adenosylhomocysteine are reduced in the face of elevated plasma homocyst(e)ine, and in the distribution of the tissue folate pools. These different metabolic profiles illustrate the potential complexities of hyperhomocyst(e)inemia in humans and suggest that comparison of the disease phenotypes of the various mouse models may be extremely useful in dissecting the underlying risk factors associated with human hyperhomocyst(e)inemia.     

Acute retinal necrosis: insights into pathogenesis from the mouse model

Acute retinal necrosis (ARN) is a relatively rare syndrome that is caused by infection with one of several members of the human herpesvirus family. ARN usually occurs in otherwise healthy patients, although it has also been observed in immunocompromised individuals. It is characterized by retinal vasculitis and haemorrhaging, areas of retinal necrosis, vitreous and aqueous inflammation and optic neuritis. It may affect one or both eyes and frequently results in severely reduced vision or blindness in the affected eye. Results using the mouse model of ARN have provided insight into the pathogenesis of this disease. However, many unanswered questions remain, such as why does only a very small fraction of individuals infected with one or more herpesvirus develop ARN? Increased understanding of the interactions of herpesviruses with T cells and cytokines may enable the development of therapeutic strategies targeted specifically to control viral infection in the eye and/or brain.     

Superantigens and retroviral infection: insights from mouse mammary tumor virus

Superantigens induce a vigorous immune response by stimulating T cells that express particular T-cell receptor Vβ chains. Mouse mammary tumor virus is a milk-transmitted retrovirus that encodes such a superantigen. Paradoxically, as discussed by Werner Held and colleagues, the strong superantigen-induced immune response permits the survival of the virus via T-cell dependent clonal expansion of infected B cells.     

Insights from mouse models of colitis

Emerging studies using mouse models of experimental colitis are defining the nature of the immunological disturbances that initiate inflammation and destruction of the intestine. A better understanding of disease-promoting and -suppressing CD4+ T cells is providing insight into the mechanisms controlling immune responses within the intestinal compartment. Moreover, a role for distinct T cell populations, including intraepithelial gammadelta T cells, in maintaining the physical integrity of the intestine was suggested by recent studies. Cytokine gene-knockout mice and anti-cytokine treatments remain important tools to define the pro- and anti-inflammatory functions of cytokines. These advances are fostering the design and evaluation of new therapeutic approaches that may eventually be applied to treat human inflammatory bowel disease.     

New insights from rodent models of fatty liver disease

Rodent models of fatty liver disease are essential research tools that provide a window into disease pathogenesis and a testing ground for prevention and treatment. Models come in many varieties involving dietary and genetic manipulations, and sometimes both. High-energy diets that induce obesity do not uniformly cause fatty liver disease; this has prompted close scrutiny of specific macronutrients and nutrient combinations to determine which have the greatest potential for hepatotoxicity. At the same time, diets that do not cause obesity or the metabolic syndrome but do cause severe steatohepatitis have been exploited to study factors important to progressive liver injury, including cell death, oxidative stress, and immune activation. Rodents with a genetic predisposition to overeating offer yet another model in which to explore the evolution of fatty liver disease. In some animals that overeat, steatohepatitis can develop even without resorting to a high-energy diet. Importantly, these models and others have been used to document that aerobic exercise can prevent or reduce fatty liver disease. This review focuses primarily on lessons learned about steatohepatitis from manipulations of diet and eating behavior. Numerous additional insights about hepatic lipid metabolism, which have been gained from genetically engineered mice, are also mentioned.     

TLRs to cytokines: Mechanistic insights from the imiquimod mouse model of psoriasis

Psoriasis is an inflammatory disease of the skin affecting 2–3% of the population, characterized by a thickening of the epidermis and immune infiltrates throughout the dermis and epidermis, causing skin lesions that can seriously affect quality of life. The study of psoriasis has historically been hampered by the lack of good animal models. Various genetically induced models exist, which have provided some information about possible mechanisms of disease, but these models rely mostly on intrinsic imbalances of homeostasis. However, a mouse model of psoriasiform dermatitis caused by the repeated topical application of Aldara? containing 5% imiquimod was described in 2009. The mechanisms of action of Aldara? are complex. Imiquimod is an effective ligand for TLR7 (and TLR8 in humans) and also interferes with adenosine receptor signaling. In addition, isostearic acid present in the Aldara? vehicle has been shown to be biologically active and of importance for activating the inflammasome. Interestingly, the repetitive application of Aldara? reveals a complex aetiology involving multiple cell types, cytokines, and inflammatory pathways. In this review, we will dissect the findings of the imiquimod model to date and ask how this model can inform us about the immunological aspects of human disease.