Transgenic mouse models of Alzheimer's disease: how useful have they been for therapeutic development?

Transgenic mice have been created in an attempt to generate models of human Alzheimer's disease, but success has been partial and unpredictable. The overall aim of this paper is to illustrate how genomics can be used in translational research, turning genetic information in the form of pathogenic mutations into clinically useful drugs against a major human disease. This paper will illustrate how genetic information allows researchers to dissect the aetiology of a disease and then replicate the disease in vivo through the process of transgenesis. The limitations of recreating a condition like Alzheimer's disease in a transgenic mouse, how far the mice have advanced understanding of the disease and how useful they have been for the development of therapeutics will then be discussed.     

What can rodent models tell us about cognitive decline in Alzheimer's disease?

The prolongation of life and the rapidly increasing incidence of Alzheimer's disease have brought to the foreground the need for greater understanding of the etiology of the disease and the means to prevent or at least slow down the process. Out of this need the transgenic mouse and the production of synthetic amyloid peptides have been developed in an attempt to create experimental models of Alzheimer's disease that will help our understanding of the cellular and molecular mechanisms by which the pathology leads to memory dysfunction and to test potential therapeutic strategies. Despite 10 or so years of reasonably intensive research with these models, both fall short of producing a viable and faithful model of the complete pathology of Alzheimer's disease and the behavioral consequences are far from modelling the progressive decline in cognitive function. Here we review the advantages and the caveats associated with the two models in terms of the pathology, the associated memory dysfunction, and the effect on synaptic plasticity. Given the more recent advances that have been made in the understanding of the neurobiological changes that occur with the disease and with the consideration of other environmental effects, which have been clearly shown to have an impact on the progression of the disease in humans, we emphasis the advantage of pharmacological or environmental in transgenic mice or rodents injected with synthetic peptides that may prove to be more fruitful in our understanding of the memory deficits associated with the disease.     

Calcium dysregulation in Alzheimer's disease: recent advances gained from genetically modified animals

Alzheimer's disease is a progressive and irreversible neurodegenerative disorder that leads to cognitive, memory and behavioural impairments. Two decades of research have implicated disturbances of intracellular calcium homeostasis as playing a proximal pathological role in the neurodegeneration associated with Alzheimer's disease. A large preponderance of evidence has been gained from the use of a diverse range of cell lines. Whilst useful in understanding the principal mechanism of neurotoxicity associated with Alzheimer's disease, technical differences, such as cell type or even the form of amyloid-beta used often underlie conflicting results. In this review, we discuss recent contributions that transgenic technology has brought to this field. For example, the triple transgenic mouse model of Alzheimer's disease has implicated intraneuronal accumulation of the amyloid-beta peptide as an initiating factor in synaptic dysfunction and behavioural deficits. Importantly, this synaptic dysfunction occurs prior to cell loss or extracellular amyloid plaque accumulation. The cause of synaptic dysfunction is unknown but it is likely that amyloid-beta and its ability to disrupt intracellular calcium homeostasis plays a key role in this process.     

The rat as an animal model of Alzheimer's disease

As a disease model, the laboratory rat has contributed enormously to neuroscience research over the years. It has also been a popular animal model for Alzheimer's disease but its popularity has diminished during the last decade, as techniques for genetic manipulation in rats have lagged behind that of mice. In recent years, the rat has been making a comeback as an Alzheimer's disease model and the appearance of increasing numbers of transgenic rats will be a welcome and valuable complement to the existing mouse models. This review summarizes the contributions and current status of the rat as an animal model of Alzheimer's disease.     

Assembly of paired helical filaments from mouse tau: implications for the neurofibrillary pathology in transgenic mouse models for Alzheimer's disease.

In Alzheimer's disease and related dementias, human tau protein aggregates into paired helical filaments and neurofibrillary tangles. However, such tau aggregates have not yet been demonstrated in transgenic mouse models of the disease. One of the possible explanations would be that mouse tau has different properties which prevents it from aggregating. We have cloned several murine tau isoforms, containing three or four repeats and different combinations of inserts, expressed them in Escherichia coli and show here that they can all be assembled into paired helical filaments similar to those in Alzheimer's disease, using the same protocols as with human tau. Therefore, the absence of pathologically aggregated tau in transgenic mice cannot be explained by intrinsic differences in mouse tau protein and instead must be explained by other as yet unknown factors.     

The non-cyclooxygenase targets of non-steroidal anti-inflammatory drugs,lipoxygenases, peroxisome proliferator-activated receptor,inhibitor of kappa B kinase,and NF kappa B,do not reduce amyloid beta 42 production

Epidemiological evidence suggests that chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of Alzheimer's disease. Recently, NSAIDs have been shown to decrease amyloid pathology in a transgenic mouse model of Alzheimer's disease. This benefit may be partially attributable to the ability of NSAIDs to selectively reduce production of the amyloidogenic A beta 42 peptide in both cultured cells and transgenic mice. Although this activity does not appear to require the action of cyclooxygenases in cultured cells, it is not known whether other NSAID-sensitive targets contribute to this A beta 42 effect. In this study, we have used both pharmacological and genetic means to determine if other known cellular targets of NSAIDs could mediate the reduction in A beta 42 secretion from cultured cells. We find that altered arachidonic acid metabolism via NSAID action on cyclooxygenases and lipoxygenases does not alter A beta 42 production. Furthermore, we demonstrate that alterations in activity of peroxisome proliferator-activated receptors, I kappa B kinase beta or nuclear factor kappa B do not affect A beta 42 production. Thus, NSAIDs do not appear to alter A beta 42 production indirectly through previously identified cellular targets and may interact directly with the gamma-secretase complex itself to affect amyloid production.     

Zebrafish as a tool in Alzheimer's disease research

Alzheimer's disease is the most prevalent form of neurodegenerative disease. Despite many years of intensive research our understanding of the molecular events leading to this pathology is far from complete. No effective treatments have been defined and questions surround the validity and utility of existing animal models. The zebrafish (and, in particular, its embryos) is a malleable and accessible model possessing a vertebrate neural structure and genome. Zebrafish genes orthologous to those mutated in human familial Alzheimer's disease have been defined. Work in zebrafish has permitted discovery of unique characteristics of these genes that would have been difficult to observe with other models. In this brief review we give an overview of Alzheimer's disease and transgenic animal models before examining the current contribution of zebrafish to this research area. This article is part of a Special Issue entitled Zebrafish Models of Neurological Diseases.     

Novel approaches for immunotherapeutic intervention in Alzheimer's disease

Immunotherapy can attenuate amyloid neuropathology and improve cognitive function in transgenic models of Alzheimer's disease. However, the first clinical trial was halted when 6% of the Alzheimer's patients developed aseptic meningoencephalitis. Postmortem analysis of two cases with meningoencephalitis showed robust glial activation, T-cell infiltration and sporadic clearance of Abeta. Interestingly, transgenic mouse models of Alzheimer's disease failed as predictors of these adverse inflammatory events. However there are now several studies with amyloid precursor protein transgenic mice that have reported an increased risk of microhemorrhages at sites of cerebrovascular amyloid deposits and because approximately 80% of Alzheimer's patient's have cerebrovascular pathology, there is concern regarding clinical trials using passive administration of humanized anti-Abeta antibodies. Although many studies have now been published on immunotherapy in mouse models, the mechanism(s) of antibody-mediated clearance of beta-amyloid from the brain, and the cause of the antibody-induced microhemorrhages remain unclear. In this review, we will discuss the most recent results from the first clinical trial, offer speculation on possible causes for the failure of the trial, review data on antibody-mediated clearance mechanisms, explore the role of complement and inflammation in the clearance of beta-amyloid, and suggest novel strategies for avoiding problems in future clinical trials. The central hypothesis being proposed in this review is that anti-Abeta antibodies delivered directly to the CNS at the sites of amyloid deposits will be far more effective at clearing Abeta and safer than active or passive immunization strategies where the majority of the antibodies are in the periphery.     

Immunotherapy as a therapeutic treatment for neurodegenerative disorders

Human neurodegenerative illnesses such as Alzheimer's disease and Creutzfeldt-Jakob disease exact an enormous cost on individuals, families and society. For these and related disorders, current treatment is largely symptomatic without influencing the underlying disease process. Until recently, the development of immunotherapeutic approaches to neurodegenerative disorders had been almost completely ignored despite growing successes against other non-infectious diseases such as cancer. However, since Schenk and colleagues described the antibody-mediated clearance of amyloid plaques in a transgenic mouse model of Alzheimer's disease, a number of studies have confirmed the feasibility of this strategy for several neurodegenerative disorders including Huntington's disease and prion diseases. These reports offer the exciting prospect that either the immune system or its derivative components can be harnessed to fight the misfolded and/or aggregated proteins that accumulate in many neurodegenerative illnesses. If the remarkable power of clonal expansion, specificity and efficiency of the immune system can successfully inactivate these abnormal proteins, real hope exists that effective immunotherapeutic treatments for neurodegenerative illnesses may be available in the near future.     

Therapeutic approaches to Alzheimer's disease

Several recent advances have provided new insights and possibilities in defining therapeutic targets for Alzheimer's disease. Of particular importance is the identification of the beta-secretase enzyme and the demonstration that immunization of a transgenic mouse model of Alzheimer's disease with Abeta(1-42) peptide can prevent or alleviate neuropathological features of the disease.     

Recent work on Alzheimer''s disease transgenics

The most significant feature of the current transgenic models of Alzheimer's disease continues to be the amyloid phenotype. In the past year, mice have been more extensively characterized in terms of the effect of amyloid accumulation on downstream events, such as neurodegeneration and behavioral changes, but the results have been complex. Genetic crosses have shown that apolipoprotein E and TGF-β1 influence the deposition event and that the presenilins act synergistically with the amyloid precursor protein in pathology development. The mice have great utility in amyloid modulation studies but are still not complete models of Alzheimer's disease.     

Calcium channel blocking as a therapeutic strategy for Alzheimer's disease: the case for isradipine

Alzheimer's disease is the most devastating neurodegenerative disorder in the elderly, yet treatment options are severely limited. The drug development effort to modify Alzheimer's disease pathology by intervention at beta amyloid production sites has been largely ineffective or inconclusive. The greatest challenge has been to identify and define downstream mechanisms reliably predictive of clinical symptoms. Beta amyloid accumulation leads to dysregulation of intracellular calcium by plasma membrane L-type calcium channels located on neuronal somatodendrites and axons in the hippocampus and cortex. Paradoxically, L-type calcium channel subtype Ca(v)1.2 also promotes synaptic plasticity and spatial memory. Increased intracellular calcium modulates amyloid precursor protein processing and affects multiple downstream pathways including increased hyperphosphorylated tau and suppression of autophagy. Isradipine is a Federal Drug Administration-approved dihydropyridine calcium channel blocker that binds selectively to Ca(v)1.2 in the hippocampus. Our studies have shown that isradipine in vitro attenuates beta amyloid oligomer toxicity by suppressing calcium influx into cytoplasm and by suppressing Ca(v)1.2 expression. We have previously shown that administration of isradipine to triple transgenic animal model for Alzheimer's disease was well-tolerated. Our results further suggest that isradipine became bioavailable, lowered tau burden, and improved autophagy function in the brain. A better understanding of brain pharmacokinetics of calcium channel blockers will be critical for designing new experiments with appropriate drug doses in any future clinical trials for Alzheimer's disease. This review highlights the importance of Ca(v)1.2 channel overexpression, the accumulation of hyperphosphorylated tau and suppression of autophagy in Alzheimer's disease and modulation of this pathway by isradipine.     

阿尔茨海默病转基因小鼠的特点和应用

建立动物模型的目的是在实验动物身上复制人类疾病的模型,用于研究人类疾病的病因、发病、病理变化以及疾病的预防和治疗。目前尚无理想的阿尔茨海默病（Alzheimer’s disease,AD）动物模型,AD实验动物模型的滞后在很大程度上制约了AD治疗药物的筛选。随着AD病因和发病机制研究的不断深入,更完善的AD动物模型也在陆续出现。近年来出现的转基因动物模型属于AD的病因模型,但也不能完整复制出AD的所有特征。最大的缺憾在于缺乏神经原纤维缠结（neurofibrillary tangles,NFTs）和在某些转基因模型中（尤其是单转基因模型）无广泛的神经元丢失。虽然用免疫组化方法检测到tau蛋白,但从未发现成对螺旋纤丝（paired helical filaments,PHF）。     

Chronic nicotine treatment reduces beta-amyloidosis in the brain of a mouse model of Alzheimer's disease (APPsw)

Alzheimer's disease neuropathology is characterised by beta-amyloid plaques and neurofibrillary tangles. Inhibition of beta-amyloid accumulation may be essential for effective therapy in Alzheimer's disease. In this study we have treated transgenic mice carrying the Swedish mutation of human amyloid precursor protein [Tg(Hu.APP695.K670N-M671L)2576], which develop brain beta-amyloid deposits, with nicotine in drinking fluid (200 microg/mL) from 9-14.5 months of age (5.5 months). A significant reduction in amyloid beta peptide 1-42 positive plaques by more than 80% (p < 0.03) was observed in the brains of nicotine treated compared to sucrose treated transgenic mice. In addition, there was a selective reduction in extractable amyloid beta peptides in nicotine treated mice; cortical insoluble 1-40 and 1-42 peptide levels were lower by 48 and 60%, respectively (p < 0.005), whilst there was no significant change in soluble 1-40 or 1-42 levels. The expression of glial fibrillary acidic protein was not affected by nicotine treatment. These results indicate that nicotine may effectively reduce amyloid beta peptide aggregation in brain and that nicotinic drug treatment may be a novel protective therapy in Alzheimer's disease.     

Amyloidogenesis in Alzheimer's disease: basic biology and animal models.

A principal neuropathological hallmark of Alzheimer's disease is deposition of beta-amyloid, composed primarily of a 4 kD peptide, A beta. This peptide is derived from larger amyloid precursor proteins. The mechanisms that are responsible for A beta formation in vivo are unknown. Recently, transgenic strategies have been employed to test several hypothetical mechanisms in order to reproduce Alzheimer's disease-specific pathology in rodents.     

The neuronal adaptor protein X11beta reduces amyloid beta-protein levels and amyloid plaque formation in the brains of transgenic mice

Accumulation of cerebral amyloid beta-protein (Abeta) is believed to be part of the pathogenic process in Alzheimer's disease. Abeta is derived by proteolytic cleavage from a precursor protein, the amyloid precursor protein (APP). APP is a type-1 membrane-spanning protein, and its carboxyl-terminal intracellular domain binds to X11beta, a neuronal adaptor protein. X11beta has been shown to inhibit the production of Abeta in transfected non-neuronal cells in culture. However, whether this is also the case in vivo in the brain and whether X11beta can also inhibit the deposition of Abeta as amyloid plaques is not known. Here we show that transgenic overexpression of X11beta in neurons leads to a decrease in cerebral Abeta levels in transgenic APPswe Tg2576 mice that are a model of the amyloid pathology of Alzheimer's disease. Moreover, overexpression of X11beta retards amyloid plaque formation in these APPswe mice. Our findings suggest that modulation of X11beta function may represent a novel therapeutic approach for preventing the amyloid pathology of Alzheimer's disease.     

Mitochondrial Abeta: a potential cause of metabolic dysfunction in Alzheimer's disease

Deficits in mitochondrial function are a characteristic finding in Alzheimer's disease (AD), though the mechanism remains to be clarified. Recent studies revealed that amyloid beta peptide (Abeta) gains access into mitochondrial matrix, which was much more pronounced in both AD brain and transgenic mutant APP mice than in normal controls. Abeta progressively accumulates in mitochondria and mediates mitochondrial toxicity. Interaction of mitochondrial Abeta with mitochondrial enzymes such as amyloid beta binding alcohol dehydrogenase (ABAD) exaggerates mitochondrial stress by inhibiting the enzyme activity, releasing reactive oxygen species (ROS), and affecting glycolytic, Krebs cycle and/or the respiratory chain pathways through the accumulation of deleterious intermediate metabolites. The pathways proposed may play a key role in the pathogenesis of this devastating neurodegenerative disorder, Alzheimer's disease.     

Alzheimer's amyloid story finds its star

Beta-amyloid peptides (Abeta) have been genetically implicated as the cause of Alzheimer's disease, but the causality of amyloid deposited as plaques has been challenged. The controversial role of amyloid peptides in Alzheimer's disease has been highlighted in a recent paper from Lesne and colleagues, who applied Koch's postulates to cast a specific memory-deficit-inducing oligomer species as a central player causing memory loss. These authors used a transgenic mouse model to identify a specific type of aggregate that emerges with cognitive deficits and is capable of transmitting a spatial memory defect to unimpaired animals.