Access the full text.
Sign up today, get DeepDyve free for 14 days.
SAGE-Hindawi Access to Research International Journal of Alzheimer’s Disease Volume 2010, Article ID 528474, 11 pages doi:10.4061/2010/528474 Review Article 1, 2 3 1, 3 1, 2 Thorsten Koechling, Filip Lim, Felix Hernandez, and Jesus Avila Centro de Biolog´ıa Molecular “Severo Ochoa” (C.S.I.C.-U.A.M.), Facultad de Ciencias, Universidad Autonoma ´ de Madrid, 28049 Madrid, Spain CIBERNED, Centro de Investigacion ´ Biom´edica en Red de Enfermedades Neurodegenerativas, 28031 Madrid, Spain Departamento de Biolog´ıa Molecular, Universidad Autonoma ´ de Madrid, 28049 Madrid, Spain Correspondence should be addressed to Jesus Avila, email@example.com Received 10 May 2010; Accepted 17 June 2010 Academic Editor: Gemma Casadesus Copyright © 2010 Thorsten Koechling et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Alzheimer’s disease (AD) is the most frequent neurodegenerative disorder leading to dementia in the aged human population. It is characterized by the presence of two main pathological hallmarks in the brain: senile plaques containing β-amyloid peptide and neuroﬁbrillary tangles (NFTs), consisting of ﬁbrillar polymers of abnormally phosphorylated tau protein. Both of these histological characteristics of the disease have been simulated in genetically modiﬁed animals, which today include numerous mouse, ﬁsh, worm, and ﬂy models of AD. The objective of this review is to present some of the main animal models that exist for reproducing symptoms of the disorder and their advantages and shortcomings as suitable models of the pathological processes. Moreover, we will discuss the results and conclusions which have been drawn from the use of these models so far and their contribution to the development of therapeutic applications for AD. 1. Introduction: Alzheimer’s Disease, can be found post mortem mainly in the hippocampus and cerebral cortex but also in other areas of the brain important Neuropathology, and Clinical Characteristics for cognitive functioning. Senile plaques and neuroﬁbrillary tangles are the two main Early and late onset AD as well as familial and sporadic histopathological characteristics of Alzheimer’s disease. They AD are distinguished based on the time in life of the patient were described for the ﬁrst time by Alois Alzheimer in when symptoms ﬁrst occur and the involvement of gene 1907, who discovered both structures in the autopsy of a mutations or chromosomal aberrations that can be related brain from a patient who had exhibited severe cognitive to the disease, respectively. Nevertheless, in all cases the impairment and memory loss. Although these hallmarks development of histopathological and behavioral symptoms of the disease were established as long as a hundred years is similar to indistinguishable. Several genetic factors have ago, the illness was not fully recognized as such due to the been described in relation with early and late onset familial social dismissal of dementia as a normal part of the human AD, though their involvement is not per se essential for ageing process . From the late 1970s onwards however, development of the disorder, given that only about 1% of all extensive neurobiological research has been in progress cases of Alzheimer’s are familial. to understand the disease and to develop therapeutic However, studying how these genetic inﬂuences may be approaches. able to induce the symptoms characteristic for AD could Today it is widely accepted that the basis for AD is be a step towards understanding the mechanisms of the biological and that senile plaques and neuroﬁbrillary tangles disease and lead scientists towards future clinical therapeutic are responsible for the inception of the disorder and also that approaches. Late onset familial AD may involve various especially the number of NFTs is proportionally related to susceptibility genes [2, 3]. The most studied is the APOE the severity of the accompanying symptoms, such as memory e4 allele of the gene coding for Apolipoprotein E. Though loss, confusion, and cognitive failure. Plaques and tangles the underlying mechanism is still unknown, proof exists that 2 International Journal of Alzheimer’s Disease this allele causes a shift in age of onset towards a younger being paired helical ﬁlaments (PHFs), and the rest being age . In early onset familial AD, mutations have been straight ﬁlaments (SFs). PHFs are bundles made up of described in three genes involved in senile plaque formation, twisted ﬁlaments, which like SFs, are composed of aberrantly namely APP, PSEN1, and PSEN2 which encode the proteins hyperphosphorylated tau protein [9, 10]. The diameter range Amyloid precursor protein, presenilin-1, and presenilin-2, of PHFs is 8–20 nm and they exhibit periodic repeats of respectively. The presenilins are integral membrane proteins 80 nm along their length while straight ﬁlaments do not that form part of the γ-secretase complex that, after β- show this periodicity and have a diameter of 15 nm . secretase cleavage of the Amyloid precursor protein, gener- PHFs are also the components of the neuropil threads, ates the amyloid β (Aβ) fragment. Mutations in PSEN1 and which appear independently of plaques and tangles and PSEN2 are believed to possibly contribute to an increase in may be observed in an array of dystrophic neurites. Not Aβ, especially the more neurotoxic form comprised of 42 all neuronal cell types appear to develop neuroﬁbrillary amino acids, Aβ . Mutated forms of human APP have been tangles. In the cerebral cortex, all cells containing NFTs expressed in a variety of transgenic animal models to further are pyramidal neurons, while in the subcortical nuclei the the understanding of plaque formation. most aﬀected cells are the ones with extremely long axons, Other contributing factors to the pathogenesis of AD consistent with the observation of thin long neurites being are being addressed in various studies, and today lifestyle especially vulnerable to AD-related cytoskeletal changes choices, adequate nutrition, psychological well being, and . intellectual stimulation are proven to exert important inﬂu- NFTs also appear independently from the presence of ence on susceptibility to AD and other forms of dementia [5, senile plaques in other neurodegenerative disorders such 6]. The understanding and distribution of this information as Pick’s disease, Progressive supranuclear palsy , fron- may not provide a cure but help to prevent the development totemporal dementia and parkinsonism linked to chro- or lower the severity of AD symptoms in many cases. mosome 17 , meningioangiomatosis , or subacute sclerosing panencephalitis . 1.1. Senile Plaques. Senile plaques are formed via the Under normal physiological conditions however, tau is aggregation of amyloid β outside neuronal cells. While Aβ a phosphoprotein that plays an important role in a variety is a naturally occurring 4 kDa polypeptide in the brain, it of processes. Besides its crucial role in tubulin assembly and becomes neurotoxic in excess quantities or when it fails microtubule stabilization [17, 18], it is also important for the outgrowth of neurites from the cell body . Recently, to be degraded so that polymerization occurs. Extracellular plaques developing in this manner act as synaptotoxins tau has also been observed to be involved in the migration blocking the communication between neurons. of new neurons . The authors detected phosphorylated Plaques are formed mostly from Aβ derived from tau protein in newly generated neurons in two well-known amyloid precursor protein (APP) which is an integral regions of adult neurogenesis, the subventricular zone membrane protein type I of unknown function which occurs associated with the lateral ventricles and the subgranular in diﬀerent isoforms. The most common isoform which is zone of the hippocampus. In these zones, phosphorylated expressed exclusively in neurons is APP695, comprised of tau was colocalized with doublecortin, a cytoskeletal protein 695 amino acids. APP contains various domains: a single that serves as a marker for neuronal migration, while tau transmembrane domain, an extramembranous N-terminal knockout mice showed similar numbers of doublecortin- domain, and a cytoplasmic region at its C-terminus as well expressing cells but also a signiﬁcant decrease in migration of these cells. The obtained results suggest a function for tau as a signal sequence. The neurotoxic eﬀects of APP are believed to be mediated by proteolytic processing of APP in the migration of newborn neurons in adult neurogenesis. which gives rise to Aβ . β-secretase (BACE1, cleaving The modiﬁcation of the tau protein by phosphorylation enzyme of the β-site of APP) liberates the amino terminal can alter the way it interacts with microtubules, as is the fragment of Aβ while the subsequent cleavage by γ-secretase case with AD. There, hyperphosphorylation induces tau to of the resulting C-terminal fragment determines the overall dissociate from the microtubules which depolymerize while length of the amyloid peptide, giving rise to Aβ , and the the concentration of soluble tau in the cells increases. This less common but more neurotoxic form Aβ . α-secretase eﬀect contributes to the assembly of ﬁlaments and the cleavage of APP does not contribute to plaque formation creation of PHFs from the soluble pool of tau. As neu- due to the fact that this cleavage takes place inside the Aβ roﬁbrillary tangles are composed mainly of PHFs and their region of APP. Aβ is believed to be one of the principal factors number in the brain has been described to be proportional to the severity of symptoms of dementia, phosphorylation which causes neurodegeneration in Alzheimer’s disease by forming oligomeric aggregates leading to accumulation of of tau appears to play a major role in the pathogenesis of these structures in the brain . Aβ is considered to be AD. more prone to aggregation and probably acts as a catalyst for Given these observations, it would be of great interest the aggregation of Aβ . to determine the enzymes that phosphorylate tau in the brain. One of them has been identiﬁed as the kinase GSK- 1.2. Neuroﬁbrillary Tangles. Neuroﬁbrillary tangles (NFT) 3. As an example, in a Drosophila melanogaster model, are the second histopathological hallmark found in brains tau phosphorylation via its GSK-3 homologue Shaggy has been described to facilitate its aggregation to ﬁlamentous aﬀected by AD. These intraneuronal lesions consist princi- pally of aberrant ﬁlaments, the principal proportion (95%) structures . International Journal of Alzheimer’s Disease 3 For an extensive explanation of tau and its role under 2.1. Lower Eukaryote Models. Diﬀerent invertebrate models physiological and pathological conditions, see the review have been created for studying Alzheimer’s disease, the most published by our group . commonly used organism being the fruit ﬂy Drosophila An alternative interpretation of the role of phospho- melanogaster. Besides being easy to breed, manipulate, and rylated tau protein has been promoted by the group of genetically modify, D. melanogaster presents the advantage Mark A. Smith . These authors question the concept of having an extremely short development time spanning that phospho-tau is inherently toxic because of its presence only 12 days from a fertilized egg to an adult ﬂy, so the in neuroﬁbrillary tangles and must therefore be a direct generation of large numbers of oﬀspring is very easy. In mediator of the disease. Instead, tau aggregation could be one model, transgenic Drosophila expressed human wild type a response to the disease, and actually play the role of and R406 mutant tau . Although overexpression of either a protective shield against neurotoxic agents rather than tau form led to the premature death of the ﬂies, symptoms of leading to neurodegeneration. In support of this model progressive neurodegeneration were more pronounced in the Castellani and coworkers point out that NFTs, (a) are found strain carrying the mutant gene. Intriguingly, the symptoms in viable neuronal cells even in late stages of AD, (b) of neurodegeneration were not accompanied by the forma- exist in the neuronal cytoplasm for decades, (c) can be tion of neuroﬁbrillary tangles. However, when ﬂies which observed, sometimes at high concentrations, in the brains of expressed wild type tau were induced to also overexpress elderly persons who showed no signs of dementia through- the Drosophila GSK-3 homologue shaggy, neuroﬁbrillary out their lifetime, and (d) are present in neurons which lesions could be observed. These ﬁndings indicate that contain normal amounts of structurally intact microtubules higher levels of tau phosphorylation cause its aggregation . into ﬁlaments and thus indicate an important role for GSK-3 in contributing to the formation of neuroﬁbrillary tangles in AD. Drosophila was also used to investigate the 2. Animal Models for AD and neurotoxicity of human wild type and mutant tau in the early Related Tauopathies stages of embryonic development . These experiments revealed that in spite of the pan-neuronal expression of Several animal models of AD have been created in order to emulate speciﬁc features of the disease, such as its tau in these transgenic lines, diﬀerent anatomical patterns histopathological, biochemical, and behavioral characteris- of toxicity in the CNS of these ﬂies could be observed depending on whether the expressed isoform was wild tics. These models were designed to probe the pathological and biochemical changes that take place in aﬀected organ- type or mutant. While human WT tau was observed to isms throughout the progression of the disorder and to test be hyperphosphorylated at speciﬁc sites and caused severe for possible therapeutic measures to be applied in the future abnormalities in the development of the mushroom body in human patients. (MB) of the animals, the FTDP17 mutant isoform led to The usefulness of an animal model depends on its signiﬁcantly less severe aberrations in MB development. The capability of faithfully replicating the physiological processes data from these experiments in D. melanogaster suggest that take part in the progress of the disease in human that not only high levels of phosphorylation are required to mediate tau toxicity but also that modiﬁcation has to patients so that it leads to a better comprehension of the pathogenesis and ﬁnally allows developing an eﬃcient take place at speciﬁc phosphorylation sites, and that tau therapeutic approach. toxicity is cell type-dependent. Another study points in the same direction, coming to the conclusion that speciﬁc Since no other natural species spontaneously produce all of the histopathological, cognitive, and behavioral symptoms phosphorylations at various sites modulate tau toxicity in a that characterize Alzheimer’s, there was a need for the synergistic manner . development of transgenic animal models or of dietary Modeling of Aβ plaque formation in D. melanogaster manipulation of test animals which would allow reproduc- has been another objective of animal studies. The transgenic expression of human WT or mutant APP led to neuronal tion of the hallmarks of AD. From a practical viewpoint, it is of great importance to choose animals with a short lifespan death in the brain already at the larval stage of development and fast rates of ageing in order to be able to observe, in a . The severity of the symptoms was proportional to the concentration of Aβ and the C-terminal fragment of reasonable time window, processes which take from 50 to 80 years in humans to appear and develop. APP. Clues exist that the diﬀerent forms of Aβ as soluble, Each animal model has its limitations and advantages, oligomeric, and insoluble plaque deposits exhibit diﬀerent as to date, none are able to express the whole set of toxicities towards cells. This ﬂy model together with the characteristics needed to resemble full-blown AD pathology recently generated speciﬁc antibodies against the diﬀerent (Table 1). The contribution of each model to the understand- types of Aβ-aggregates [29, 30] could be used to address ing of this devastating disease, however, is immeasurable this question. D. melanogaster has also been successfully and has permitted the scientiﬁc community to establish an employed in the study of the inﬂuence of oxidative stress on the pathology of Alzheimer’s disease. Lowering the antiox- extensive base of knowledge on AD and the mechanics of the disorder. In the following, we will present the diﬀerent idant defenses of animals which expressed R406 mutant animal models which have been established so far, discuss human tau increased tau toxicity while the antioxidant α- tocopherol (vitamin E) was able to alleviate the eﬀects of tau their characteristics, advantages, and pitfalls as well as take a look at the latest developments in this ﬁeld of research. toxicity . 4 International Journal of Alzheimer’s Disease Table 1: Overview of the most widely used models for studying Alzheimer’s disease. Model Advantages Drawbacks (i) Highly evolved organism, brain anatomy, and metabolism close to humans, results often (i) Relatively long breeding/development time extrapolatable to humans Mus musculus (ii) Ethical concerns (ii) Cognitive symptoms of neurodegeneration (mouse) (iii) Not suitable for drug screening can be assessed (iv) Expensive (iii) Generation of conditional transgenic models possible (i) Ex-utero development in transparent capsule (i) Brain anatomy and genetic setup distinct from allows for live imaging of neurodegenerative Danio rerio humans processes (zebraﬁsh) (ii) Behavior not suﬃciently studied, diﬃcult to (ii) Short life cycle evaluate cognitive deﬁcits (iii) Genetic manipulation tools available (i) Simple anatomy, (i) Brain anatomy and genetics distinct from Caenorhabditis (ii) Easy laboratory culture, short life cycle humans elegans (nematode) (iii) Genetic manipulation tools highly advanced (ii) Cognitive/behavioral deﬁcits diﬃcult to assess (i) Reference model for genetic studies Drosophila (ii) Suitable for drug screening (i) Brain anatomy and genetics distinct from melanogaster (iii) Short generation times, low maintenance humans (fruit ﬂy) costs (ii) Cognitive/behavioral deﬁcits diﬃcult to assess (iv) genetic manipulation tools highly advanced (i) Direct monitoring of parameters over time (i) Organ structure not conserved, environmental possible cues/interaction with other organs are not taken In vitro cell culture (ii) Extremely valuable for high-throughput into account models screening for therapeutic drugs (ii) Ethical considerations in the case of human (iii) Easy handling, economic embryonic/fetal tissue as source material Another application of the fruit ﬂy with direct clinical in recent literature reviews [33, 34]for C. elegans and [35, 36] relevance is that of a model organism for ﬁrst round drug for D. rerio, respectively. C. elegans is a small organism with screening in AD. Given its extremely short development a short life span that allows for high throughput manipu- period, being an organism which is cheap and easy to manip- lation and drug screening applications, while the zebraﬁsh, ulate even in large numbers and the low ethical restrictions another well-suited organism for studying neurodegenera- when working with ﬂies, D. melanogaster presents an overall tion, presents the advantage of being completely transparent advantageous choice. In a very recent study, a Drosophila in its larval development state, allowing continuous in vivo model was described using the ﬂy’s notal bristles as a tool observation of processes taking place in its exposed nervous for assessing tau-induced toxicity . The authors propose system. Paquet and coworkers  generated a ﬂuorescently the use of this model for the screening of possible drugs for labeled tau transgenic zebraﬁsh model. Using this animal, use in AD therapy. While the fruit ﬂy presents a number the authors were able for the ﬁrst time to trace directly of advantages as a suitable animal model for AD, there are neurodegenerative processes taking place in the ﬂuorescently also certain pitfalls. One major restriction when trying to stained larvae and to visualize the resulting neuronal cell extrapolate experimental data gained with D. melanogaster death via time lapse microscopy in vivo. In addition, they is its signiﬁcantly diﬀerent brain structure from humans, as employed this novel model as a tool for drug screening it does not possess a hippocampus for example. Due to its of GSK-3 inhibitors and have validated one promising small size the Drosophila brain is also diﬃcult to analyse compound termed AR-534. using stains for identiﬁcation of distinct regional expression of histopathological markers. Last, memory impairment 2.2. Mouse Models. Choosing a neuroanatomy which more and cognitive deﬁcits in such a phylogenetically distant closely resembles the human brain, several mouse models organism are diﬃcult to extrapolate to compare with human of AD and other tauopathies have been developed in the conditions. last ﬁfteen years. Earlier models fell into two main groups, To widen the understanding of the cellular mechanisms according to the AD hallmark lesion (amyloid plaques or involved in AD and to aid in the search for pharmacological neuroﬁbrillary tangles) mimicked in each model, but more compounds that could be in the beneﬁt of therapeutic recent approaches have generated models exhibiting both interventions for tauopathies, other lower organisms are features simultaneously. being employed as models for the disease. Two of the most widely used animal models at the time are the roundworm Caenorhabditis elegans and the zebraﬁsh (Danio rerio). The 2.2.1. APP/Aβ Modeling. Several transgenic mouse lines have advances that these models provided have been summarized been generated which express one of the mutant forms of International Journal of Alzheimer’s Disease 5 APP. Most of these transgenic lines exhibited senile plaques D664 cleavage site of APP would not be a suitable target for as Aβ depositions and also the characteristic behavioral the development of therapeutic interventions. deﬁcits reminiscent of AD in animal models. The ﬁrst of the Recently, the diﬀerential toxicity of soluble Aβ oligomers transgenic animals expressed the human mutant V717F APP and ﬁbrillary Aβ plaques has been discussed . In a form driven by the platelet-derived growth factor (PDGF) study with mice, animals which overexpressed the “Arctic” mini promoter . Aβ plaque formation was observed in mutation were compared to mice overexpressing wildtype the test animals as well as memory impairment, especially Aβ . While the mutant Aβ (AβE22G) led to the marked related to spatial learning. When compared to wild type formation of amyloid plaques, it also lowered the con- mice, the transgenic animals showed a signiﬁcantly more centration of a speciﬁc nonﬁbrillar Aβ-assembly (Aβ 56). severe decline in memory as assessed by a modiﬁcation Remarkably, both strains showed similar behavioral and of the Morris water maze experiment. Another model neuronal deterioration when normalized for Aβ 56 levels, SW expressed a diﬀerent mutant APP form, the APP (Swedish) while the number of plaques was very diﬀerent. The authors double mutation inserted into a hamster prion protein of the study concluded that Aβ 56 concentrations are a more (PrP) cosmid vector . The animals presented memory suitable marker for AD-related functional deﬁcits than the and spatial learning deﬁcits at 9 months of age. β-amyloid amount of Aβ deposited in the form of plaques. Therapeutic concentrations increased ﬁvefold in Aβ and 14-fold in approaches that lead to the breakdown of ﬁbrillary Aβ Aβ , and the deposits could be stained with Congo red but possibly increase the levels of soluble oligomers could especially in the cortical and limbic regions of the brain. therefore be counterproductive. In a third model that overexpressed APP sevenfold, amyloid In view of these data, therapeutic interventions which plaques appeared as soon as at six months of age in the tested block the production of Aβ monomers and soluble oligomers mice. In contrast to the other two cited studies, these mice should be explored. This could be achieved by inhibiting showed signiﬁcant neuronal cell death besides the plaque the secretases involved in APP processing. These enzymes deposits, speciﬁcally of pyramidal neurons in the CA1 region however are involved in other physiological processes as of the hippocampus, with the plaques seemingly aﬀecting well, and it may therefore be detrimental to indiscriminately cell integrity in the adjacent neurons. Several experiments reduce their activity. Recent strategies avoid this problem, as in transgenic mice have shown that amyloid plaque forma- in the case of some nonsteroidal anti-inﬂammatory drugs tion can promote tau pathology [40, 41]. When crossing (NSAIDs) which do not alter secretase activity but alter its human APP transgenic mice with tau expressing strains, or cleavage site speciﬁcity resulting in the generation of the less administering Aβ intracerebrally, tau phosphorylation was toxic 38 residue Aβ instead of the highly amyloidogenic Aβ42 enhanced and NFT depositions increased in concentration. . The introduction of immunotherapeutic treatments Interestingly however, when hAPP mice were crossed with could also lead to the speciﬁc elimination of Aβ oligomers tau knockout animals, no memory or learning deﬁcits could and might prevent their formation. Positive eﬀects of this be detected in spite of the massive deposition of plaques in approach have been described in a transgenic mouse model these mice . These ﬁndings underscore the importance of  and were also assessed in humans in a small cohort of the presence of tau protein for the induction of the disease as AD patients . in this animal model amyloid-mediated toxicity was nulliﬁed by the absence of tau. The level of neurotoxicity exerted by 2.2.2. NFT Modeling. Transgenic mice carrying cDNAs Aβ also depends on its length as was revealed in a transgenic which encode either the largest or the smallest human tau mouse study carried out by McGowan and coworkers isoform have been generated. Later, mouse models which , as transgenic mice which express only Aβ did not express the mutant isoform of tau found in FTDP-17 patients develop any senile plaques while Aβ -expressing animals were also developed, as well as mice that model the disease via did. the overexpression of certain kinases which play a key role in Adiﬀerent mechanism of proteolytic modiﬁcation of the hyperphosphorylation of tau in AD and related disorders. the Amyloid precursor protein is the cleavage at aspartate The ﬁrst transgenic mouse which expressed the longest residue 664 (D664) by caspases. Previous studies suggested tau isoform under control of the human Thy-1 promoter that this cleavage, alternative to the described catalytic showed tau phosphorylation at sites which are usually found mechanisms involving secretases, could play a key role in the to be modiﬁed in PHFs and presented localization of human pathogenesis of AD [44, 45]. To address this question, Harris tau in neuronal soma, axons, and dendrites. These mice and coworkers used two transgenic mouse lines carrying the exhibit modest expression of human tau protein (approxi- APP gene with (B254) and without (J20) the caspase-speciﬁc mately 10% of total tau in the animals) and did not exhibit cleavage site and studied the possible implication of the neuroﬁbrillary tangles . However, the histopathology resulting products, the C31 and Jcasp fragments, in AD . observed in these animals reﬂects an early stage of AD prior Although these products had been described before to cause to the formation of neuroﬁbrillary tangles, in which hyper- cell death in vitro, in these in vivo experiments, histological phosphorylated forms of tau are localized in the soma and and behavioral assessment of the test animals did not reveal dendrites of neuronal cells. In another mouse model in which signiﬁcant diﬀerences between the B254 and J20 mice. The the shortest human tau isoform was overexpressed  authors came to the conclusion that caspase cleavage of APP under the murine HMG CoA reductase promoter, transgenic does not play a critical role in the generation of AD-related tau could be detected in the somatodendritic compartment, abnormalities in these transgenic mice, and that therefore the although again no NFT formation was observed. Subsequent 6 International Journal of Alzheimer’s Disease transgenic mouse models were designed using stronger in human patients, senile plaques and neuroﬁbrillary tangles, promoters, resulting in increased expression of human tau and furthermore, synaptic plasticity and neuronal long-term in these animals until eventually brain tau aggregates could potentiation were impaired in these animals in a manner be detected, although the formation of NFTs still remained which could be related to Aβ formation. elusive [54, 55]. These models showed not only AD-like In 2002, a transgenic mouse was created that expressed symptoms in brain cells but also exhibited spheroidal tau tau bearing the P301S mutation. This mutation is responsible aggregates in the spinal cord resulting in motor symptoms in in humans for an early onset of the pathological signs of the animals characteristic more of amyotrophy . While FTDP-17 . In this model, numerous PHFs consisting transgenic mice with excessive overexpression of human of tau ﬁlaments could be detected in the brains and spinal tau are not viable, lines that overexpress tau less than cords of the animals. Another observation was that motor tenfold have been generated and tau inclusions have been neurons were the cell type where the highest concentrations observed in cortical, brain stem, and spinal cord neurons, of tau could be detected. Consistent with the ﬁndings in accompanied by other symptoms such as axon degeneration, human patients where the P301S mutation is related with decrease of microtubules, and motor deﬁcits. Staining of an earlier onset of FTDP-17 as compared to the P301L the inclusions with the AD pathology-speciﬁc dyes Congo mutation, neuronal cell death was highly elevated (49%) in red and Thioﬂavin S revealed increasing insolubility of mice which overexpressed human P301S tau. Colocalization the aggregates over time and NFT-like inclusions could be of hyperphosphorylated tau deposits and MAP kinases detected in old animals (18 to 20 months) . Other hinted at the possible implication of these enzymes in models with the tau gene under the control of the PrP tau modiﬁcation. In another study which compared the promoter led to the expression of high levels in certain development of neurodegenerative signs in P301S mutant types of neurons and glial cells. Here, ﬁbrillary structures transgenic and wild type mice, neuroﬁbrillary lesions could couldbedetectedinglial cells(oligodendrocytes)aswellas be detected in the transgenic animals at the age of 9 to 12 neurons . The phenotype however was still not severe. months, accompanied by the massive loss of hippocampal In a mouse model expressing three isoforms of human tau and cortical neurons . Interestingly, synapse loss in the simultaneously, structures were observed which were similar hippocampus and deﬁcits in synaptic function could be to the astrocytic plaques that characteristically appear in the observed long before the formation of NFTs, at about three gray matter in cases of Corticobasal Degeneration (CBD), months of age. Given that early microglial activation was also although neuronal cells were not equally aﬀected, as they did observed and that tau pathology could to some extent be not show any ﬁbrillary lesions . reverted by administration of the immunosuppressive drug While to this day no mutations have been found in FK506, the authors of the study established a link between the tau-encoding MAPT gene in AD patients, molecular neuroinﬂammation and the early stages in the development analysis of another tauopathy, frontotemporal dementia with of tauopathies. parkinsonism linked to chromosome 17 (FTDP-17), has The implication of an improperly controlled cell cycle revealed characteristic mutations in this gene. Some of them in neurodegenerative diseases has also been described in like the P301L or the R406W mutations have been observed the literature . In degenerating neurons elevated con- to lower tau’s potential to promote microtubule stability . centrations of proteins associated with the cell cycle such In mouse models expressing a human tau isoform containing as cyclins, cyclin-dependent kinases, and the products of the P301L mutation , reviewed in , it was found that proto-oncogenes such as c-myc, can often be detected. Two this mutation reduces the aﬃnity of tau for microtubules. studies investigate the eﬀects of cell cycle reentry mediated In one study, the mice showed NFTs in the brain as well by transduction with c-myc, using an in vitro cell culture as in the spinal cord alongside with a substantial reduction model aswellasatransgenic mousemodel . in the number of motor neurons . Furthermore, the Induced cell cycle reentry led to the death of neurons, animals developed severe behavioral deﬁcits which emulate gliosis, and cognitive impairment in the mouse model, thus neurological symptoms of the disease in humans. In another indicating that this loss of control in mature, postmitotic study also employing mice overexpressing human tau with neurons may contribute to the pathogenesis of diseases like the P301L mutation , short tau ﬁlaments were isolated Alzheimer’s. Interestingly, forced cell cycle re-entry led to the from the brains of the test animals. Interestingly, one study phosphorylation of tau and to the formation of tangle-like revealed that when the expression of mutant P301L tau was structures in the in vitro model, providing further evidence suppressed after a period of overexpression, the behavioral for a possible causal connection between the cell cycle and symptoms in these mice could be reversed, while the insol- AD. uble NFTs were not removed but continued to accumulate. Another interesting study addresses the possible contri- This result hints at the possibility that soluble tau rather than bution of insulin to the pathogenesis of AD . As insulin its ﬁbrillary deposits is the cause of neuronal cell death in has been described to be involved in the metabolism of Alzheimer’s disease . A triple transgenic mouse model both Aβ and tau, the researcher studied the possible eﬀect SW expressing the mutant transgenes PS1 (M146V), APP , of artiﬁcially induced Diabetes mellitus (DM) on the brain and P301L tau was generated by the group of LaFerla to cells of pR5 transgenic mice which expressed the P301L examine the interactions between beta-amyloid, neuronal human mutant tau and produced neuroﬁbrillary tangles. dysfunction and neuroﬁbrillary tangles . These 3xTg-AD After drug induced-insulin depletion, tau phosphorylation mice developed both of the classical hallmarks of Alzheimer’s increased in both wild type controls and transgenic mice, International Journal of Alzheimer’s Disease 7 though remarkably only the transgenic animals produced the suppression of the cognitive deﬁcits. These ﬁndings massive deposits of nonsoluble hyperphosphorylated tau further support the potential of GSK-3 inhibitors in the protein. The authors came to the conclusion that DM is treatment of AD . capable of triggering an earlier onset of a preexisting tau To further study the involvement of GSK-3, transgenic pathology in susceptible animals and that diabetes might mice that overexpress GSK-3β were crossed with FTDP- cause an abnormal phosphorylation of tau via the elevation 17 mutant tau mice . This AD animal model, termed of glucose levels. Given the high rates of comorbidity of GSK-3/VLW, shows tau hyperphosphorylation in CA1 hip- AD and DM in the human population, this line of research pocampal neurons, the region where the expression patterns deserves further investigation as it might unveil new insights of both transgenes overlap. Tau ﬁlaments with a PHF-like on the pathogenesis of AD. structure were found in GSK-3/VLW mice but not in single In a complex yet very elegant survey, a genome wide transgenic mice expressing either GSK-3β or FTDP-17 tau search strategy employing lentivectors led to the identiﬁ- alone. PHF-like ﬁlament formation in GSK-3/VLW mice cation of a retroposed gene in mouse . This Rps23r1 was accompanied by thioﬂavin-S staining, indicating the gene normally encodes for the ribosomal protein S23 but presence of senile plaques. All these data suggest that there is in the retroposed form is transcribed in the reversed sense, a synergistic contribution of both types of tau modiﬁcation, expressing a functional protein which is localized integrated hyperphosphorylation and missense mutations, to induce in cell membranes of the cerebral cortex and hippocampus. aberrant tau aggregation. Intriguingly, overexpression of Rps23r1 reduced levels of The same animal model has been utilized to study Aβ, GSK-3 activity, and tau phosphorylation. The proposed the possible eﬀects of lithium, a GSK-3 inhibitor used for mechanism of this eﬀect consists of an initial interaction with treating aﬀective disorders with well-documented eﬀects in adenylate cyclases upregulating cellular cAMP levels, which humans . Two questions were addressed: ﬁrst, whether in turn activates protein kinase A (PKA). This activation chronic lithium treatment is able to prevent the formation results in the inhibition of GSK-3, a kinase that is involved of aberrant tau aggregates (formed by overexpression of in tau phosphorylation and Aβ generation. FTDP-17 tau and GSK-3β); and second, whether lithium can Given that these aberrant phosphorylations of tau play revert already formed tau aggregates and NFTs to achieve a key role in the development of Alzheimer’s disease, their clearance in aged animals. The results indicated that another important strategic approach is to identify the lithium is capable of preventing the development of tau phosphorylation sites that are connected to the formation pathology when administered early in disease progression. of aggregates and to identify the responsible enzymes and On the other hand, if lithium administration is initiated pathways for these tau modifying reactions, namely, the at late stages, tau hyperphosphorylation is reduced but tau kinases and phosphatases. aggregation cannot be reversed. The data supports studies The ﬁrst generation of transgenic mice expressing GSK- describing novel GSK-3 inhibitors as new pharmacological 3β, a kinase involved in many physiological pathways, was treatments of this kind of neurodegenerative disorders, as generated using both ubiquitous or CNS-speciﬁc promoters reviewed byAvila and Hernandez ´ . . In all cases however, though slight increases in the A second transgenic animal expressing a constitutively phosphorylation levels of tau could be observed, no overex- active form of the kinase, GSK-3β(S9A), has been cross-bred pression of the enzyme took place. This is probably due to with transgenic mice that overexpress the longest human tau the narrow window of concentrations in which GSK-3 can be isoform . The number of axonal enlargements present expressed in cells, below and above which the lack or excess and the motor impairment typical for these tau transgenic of GSK-3 activity proves lethal. animals were reduced in the double transgenic mice . Considering the narrow concentration range of GSK-3 Thus, taking into account all these data it seems that GSK- that permits cell viability, a model was created with GSK- 3 could have diﬀerent functions in diﬀerent neurons and 3 gene expression adjustable by means of a conditional in diﬀerent regions of the brain, while the hippocampal tetracycline regulated system under the control of the CaM dentategyrus seemstobemoresusceptible to degener- kinase II α-promoter . The advantage of animal models ation in transgenic mice overexpressing GSK-3β . A employing the tetracycline regulation system lies in the recent publication examines the possible role of GSK-3 in possibility to carry out reversible studies . In this tau phosphorylation in the dentate gyrus . Previously mouse model, GSK-3β overexpression was conﬁned to a generated transgenic mice which overexpress GSK-3 in the particular set of cortical and hippocampal neurons. The dentate gyrus were crossed with a tau knockout strain in overexpression of the kinase led to hyperphosphorylation of order to verify if GSK-3 mediated phosphorylation of tau is tau as detected by speciﬁc antibodies and showed how tau the cause of neurodegeneration in the dentate gyrus. When phosphorylation lowers its aﬃnity for microtubule binding. compared to tau-expressing control animals, the authors Behavioral deﬁcits related to Alzheimer’s disease however, observed that the signs of neurodegenerative damage were could be observed in this animal model by applying the signiﬁcantly attenuated in the absence of tau. Therefore, Morris water maze test . In spite of these ﬁndings, hyperphosphorylation of tau is proposed to be a causal factor the correlated deposition of insoluble tau neuroﬁbrillary of the histopathological lesions found in the animals. tangles could not be observed. The shutdown of GSK- Very recently, the role of caspases in AD was reevaluated 3 overexpression in turn leads to normal GSK-3 activity, in a study by Calignon and coworkers . Using the normal phospho-tau levels, diminished neuronal death, and transgenic Tg4510 mouse strain, the researchers observed 8 International Journal of Alzheimer’s Disease that tangle free cells which showed caspase activation formed immunomarkers of ES cells . Later, the authors were able NFTs within 24 hours. Furthermore, administration of wild to generate iPS cells from adult human dermal ﬁbroblasts type tau into wild type animals led to caspase activation using the same four factors . Today, several cell lines and eventually to tangle formation. The data from this study speciﬁc for various neurodegenerative diseases have been suggest that caspase activation of tau could be a direct cause generated with the objective of creating human in vitro of tangle formation, and as has been pointed out in various models. Examples are Amyotrophic lateral sclerosis (ALS) recent articles, that the AD typical neuroﬁbrillary deposits , Parkinson disease (PD), and Huntington disease (HD), are the ﬁnal histological outcome of a neurodegenerative reviewed in . In the case of ALS, Dimos and coworkers process, rather than the cause of it.  were able to derive iPS cells from ﬁbroblasts of an 82- year-old patient suﬀering from the disease and subsequently diﬀerentiate these iPS cells into motor neurons, the cell 3. Cell Culture Models type aﬀected by ALS. To date, the generation of Alzheimer’s While research models in animals allow studies in the whole speciﬁc iPS cells has not been published, but their generation organism within a reasonable time, there also exists a need and diﬀerentiation to neuronal types involved in disease for the possibility to investigate disease-related processes in progression hopefully will be accomplished soon, oﬀering a human cells. Live human neuronal cells however are diﬃcult novel tool to study the pathological processes, such as tau phosphorylation and tangle formation, which so far have not to access for study. Therefore, recently cell culture-based approaches are being developed, relying on the derivation been completely recapitulated in animal models. and propagation of neuronal cells from diﬀerent types of Another strategy is the use of fetal human neural stem cells(hNSC)tocreatecellmodelsbydiﬀerentiation of human tissue. One widely employed model for neuronal cells in culture these cells to neuronal types of interest. We have established is the human neuroblastoma line SHSY5Y, which was used a method for the diﬀerentiation of hNSC to postmitotic to elucidate the role of leptin in Alzheimer’s disease. Leptin neurons which express the neuronal markers tau and βIII- has recently been proposed as another factor related to tubulin. These neurons were derived from human fetal forebrain tissue  and are viable in cell culture for the susceptibility of contracting AD. It is an endocrine hormone with implications in food intake regulation as weeks. This model permits the study of eﬀects of candidate well as processes of learning and memory, for example, therapeutic drugs on tau expression or phosphorylation state. Furthermore, these cells can be transduced with viral in long-term potentiation (LTP) . Epidemiological data from human populations suggest a signiﬁcantly lower risk vectors to overexpress AD-related genes, such as those of developing AD for people with higher leptin blood encoding tau or GSK-3 allowing the study of the consequent levels . The mechanism of action is probably the same alterations, including the formation of tangles and plaques. as one described for the physiologically closely related Additionally, the eﬀect of tau-overexpression on neural peptide insulin. Experiments with diﬀerentiated SHSY5Y stem cells (in their undiﬀerentiated state) is an interesting human neuroblastoma cells indicate that both compounds topic, as brains aﬀected by AD show high levels of tau are capable of reducing the level of tau phosphorylation phosphorylation in regions, such as the hippocampus, where neural stem cells reside and are involved in adult neurogene- via inactivation of GSK3-β . Another study revealed a possible protective eﬀect of leptin on neuronal cells against β- sis. As research in neural stem cells and neurodiﬀerentiation amyloid toxicity . In as SHSY5Y cell culture model as well continues to make technological leaps, further contributions to Alzheimer research can be expected soon by means of as in a transgenic mouse model, leptin was found to reduce toxic Aβ levels. Leptin reduces the activity of β-secretase, one creation of human cell models that imitate speciﬁc aspects of the enzymes that cleaves APP, which could probably be the of the disease. underlying mechanism of the Aβ reducing eﬀect of leptin. Recently, the applicability of cell culture models has 4. Conclusion been vastly improved by the possibility of deriving patient- speciﬁc cell lines that can be propagated in vitro. Patient- In summary, a variety of animal models have been generated speciﬁc ﬁbroblasts for example, can be reprogrammed to which reproduce either the Aβ or tau histopathological induced pluripotent stem (iPS) cells and then diﬀerentiated hallmark lesions of AD as well as transgenic animals which into neuronal cell types similar to those found in the exhibit both features simultaneously. Some of these models hippocampus or cerebral cortex. This allows the generation reproduce the lesions as well as the related behavioral impair- of cell models that reproduce certain disease-speciﬁc features ments, while suggesting that both plaques and tangles may in vitro, without ethical concerns and which are easily have synergistic eﬀects in driving the disorder rather than accessible for analysis and manipulation . developing independently from each other. This observation The groundbreaking work in iPS generation was con- is strengthened by the notion that the transgenic mouse ducted by the group of Yamanaka, who succeeded in creating models most successfully reproducing AD-like pathology are pluripotent stem cells ﬁrst by transducing mouse embryonic the ones which combine overexpression of tau and APP, ﬁbroblasts with a set of four genes encoding the factors like the 3xTg-AD mice . The animal models shed light Oct3/4, Sox2, c-Myc, and Klf4. When grown under culture on mechanisms of progression of tauopathies and their conditions for embryonic stem (ES) cells, these iPS cells application as drug screening systems pave the way for showed the morphological traits, growth potential, and the development of future treatments of dementia. Due to International Journal of Alzheimer’s Disease 9 the additional need for human models combined with the  D. J. Selkoe and M. B. Podlisny, “Deciphering the genetic basis of Alzheimer’s disease,” Annual Review of Genomics and impossibility of conducting basic research in humans in vivo, Human Genetics, vol. 3, pp. 67–99, 2002. the use of iPS cells and neural stem cell cultures derived  J. Halper, B. W. Scheithauer, H. Okazaki, and E. R. Laws Jr., from human fetal and adult tissue is being established as an “Meningio-angiomatosis: a report of six cases with special alternative and complementary route. While this approach reference to the occurrence of neuroﬁbrillary tangles,” Journal does not hold the advantages of conserving the integrity of of Neuropathology and Experimental Neurology, vol. 45, no. 4, the biological system under study, they do allow the study pp. 426–446, 1986. of molecular interaction and biochemical pathways in an all-  M. M. Paula-Barbosa, R. Brito, C. A. Silva, R. Faria, and human system, a point of high relevance due to the human C. Cruz, “Neuroﬁbrillary changes in the cerebral cortex of a speciﬁcity of many aspects of AD. patient with subacute sclerosing panencephalitis (SSPE),” Acta Neuropathologica, vol. 48, no. 2, pp. 157–160, 1979. References  M. D. Weingarten, A. H. Lockwood, S. Y. Hwo, and M. W. Kirschner, “A protein factor essential for microtubule  N. S. Whaley, Senility, confusion, debate, fear: conceptualizing assembly,” Proceedings of the National Academy of Sciences of Alzheimer’s disease and the history of senile dementia, Thesis, the United States of America, vol. 72, no. 5, pp. 1858–1862, Drew University, Madison, NJ, USA, 2002.  A. Serretti, P. Artioli, R. Quartesan, and D. De Ronchi,  R. Takemura,S.Okabe,T.Umeyama,Y.Kanai,N.J.Cowan, “Genes involved in Alzheimer’s disease, a survey of possible and N. Hirokawa, “Increased microtubule stability and alpha candidates,” Journal of Alzheimer’s Disease,vol. 7, no.4,pp. tubulin acetylation in cells transfected with microtubule- 331–353, 2005. associated proteins MAP1B, MAP2 or tau,” Journal of Cell  A. D. Roses and A. M. Saunders, “Perspective on a patho- Science, vol. 103, no. 4, pp. 953–964, 1992. genesis and treatment of Alzheimer’s disease,” Alzheimer’s and  C.-W. A. Liu, G. Lee, and D. G. Jay, “Tau is required for Dementia, vol. 2, no. 2, pp. 59–70, 2006. neurite outgrowth and growth cone motility of chick sensory  A. S. Khachaturian, C. D. Corcoran, L. S. Mayer, P. P. Zandi, neurons,” Cell Motility and the Cytoskeleton,vol. 43, no.3,pp. and J. C. S. Breitner, “Apolipoprotein E ε4 count aﬀects age at 232–242, 1999. onset of Alzheimer disease, but not lifetime susceptibility: the  A. Fuster-Matanzo,E.G.deBarreda,H.N.Dawson, M. P. Cache County Study,” Archives of General Psychiatry, vol. 61, Vitek, J. Avila, and F. Hernandez, ´ “Function of tau protein in no. 5, pp. 518–524, 2004. adult newborn neurons,” FEBS Letters, vol. 583, no. 18, pp.  S. L. Tyas, D. A. Snowdon, M. F. Desrosiers, K. P. Riley, and W. 3063–3068, 2009. R. Markesbery, “Healthy ageing in the Nun Study: deﬁnition  G. R. Jackson, M. Wiedau-Pazos, T.-K. Sang et al., “Human and neuropathologic correlates,” Age and Ageing, vol. 36, no. wild-type tau interacts with wingless pathway components 6, pp. 650–655, 2007. and produces neuroﬁbrillary pathology in Drosophila,” Neu-  J. Gotz ¨ and L. M. Ittner, “Animal models of Alzheimer’s disease ron, vol. 34, no. 4, pp. 509–519, 2002. and frontotemporal dementia,” Nature Reviews Neuroscience,  J. Avila, J. J. Lucas, M. Per ´ ez, and F. Hernandez, ´ “Role of tau vol. 9, no. 7, pp. 532–544, 2008. protein in both physiological and pathological conditions,”  J. Nunan and D. H. Small, “Regulation of APP cleavage by α- Physiological Reviews, vol. 84, no. 2, pp. 361–384, 2004. , β-and γ-secretases,” FEBS Letters, vol. 483, no. 1, pp. 6–10,  H.-G. Lee, G. Perry, P. I. Moreira et al., “Tau phosphorylation in Alzheimer’s disease: pathogen or protector?” Trends in  J. T. Jarrett and P. T. Lansbury Jr., “Seeding “one-dimensional Molecular Medicine, vol. 11, no. 4, pp. 164–169, 2005. crystallization” of amyloid: a pathogenic mechanism in  R. J. Castellani, A. Nunomura, H.-G. Lee, G. Perry, and M. A. Alzheimer’s disease and scrapie?” Cell, vol. 73, no. 6, pp. 1055– Smith, “Phosphorylated tau: toxic, protective, or none of the 1058, 1993. above,” Journal of Alzheimer’s Disease, vol. 14, no. 4, pp. 377–  K. S. Kosik, C. L. Joachim, and D. J. Selkoe, “Microtubule- 383, 2008. associated protein tau (τ) is a major antigenic component  C. W. Wittmann, M. F. Wszolek, J. M. Shulman et al., of paired helical ﬁlaments in Alzheimer disease,” Proceedings “Tauopathy in Drosophila: neurodegeneration without neu- of the National Academy of Sciences of the United States of roﬁbrillary tangles,” Science, vol. 293, no. 5530, pp. 711–714, America, vol. 83, no. 11, pp. 4044–4048, 1986.  R. A. Crowther, “Structural aspects of pathology in  S. Kosmidis, S. Grammenoudi, K. Papanikolopoulou, and E. Alzheimer’s disease,” Biochimica et Biophysica Acta, vol. M. C. Skoulakis, “Diﬀerential eﬀects of tau on the integrity 1096, no. 1, pp. 1–9, 1991. and function of neurons essential for learning in Drosophila,”  M. Goedert, M. G. Spillantini, N. J. Cairns, and R. A. Journal of Neuroscience, vol. 30, no. 2, pp. 464–477, 2010. Crowther, “Tau proteins of Alzheimer paired helical ﬁlaments:  M. L. Steinhilb, D. Dias-Santagata, T. A. Fulga, D. L. Felch, and abnormal phosphorylation of all six brain isoforms,” Neuron, M. B. Feany, “Tau phosphorylation sites work in concert to vol. 8, no. 1, pp. 159–168, 1992. promote neurotoxicity in vivo,” Molecular Biology of the Cell,  E. Braak, K. Griﬃng, K. Arai, J. Bohl, H. Bratzke, and H. Braak, vol. 18, no. 12, pp. 5060–5068, 2007. “Neuropathology of Alzheimer’s disease: what is new since  A. Fossgreen, B. Bru ¨ckner,C.Czech,C.L.Masters,K. A. Alzheimer?” European Archives of Psychiatry and Clinical Beyreuther, and R. Paro, “Transgenic Drosophila expressing Neuroscience, vol. 249, no. 3, pp. III14–III22, 1999. human amyloid precursor protein show γ-secretase activity  D. R. Williams and A. J. Lees, “Progressive supranuclear palsy: and a blistered-wing phenotype,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. clinicopathological concepts and diagnostic challenges,” The Lancet Neurology, vol. 8, no. 3, pp. 270–279, 2009. 23, pp. 13703–13708, 1998. 10 International Journal of Alzheimer’s Disease  B. O’Nuallain and R. Wetzel, “Conformational Abs recog-  J. A. Harris, N. Devidze, B. Halabisky et al., “Many neuronal nizing a generic amyloid ﬁbril epitope,” Proceedings of the and behavioral impairments in transgenic mouse models of National Academy of Sciences of the United States of America, Alzheimer’s disease are independent of caspase cleavage of the vol. 99, no. 3, pp. 1485–1490, 2002. amyloid precursor protein,” Journal of Neuroscience, vol. 30, no. 1, pp. 372–381, 2010.  G. Habicht, C. Haupt, R. P. Friedrich et al., “Directed selection of a conformational antibody domain that prevents mature  L. Mucke, E. Masliah, G.-Q. Yu et al., “High-level neuronal amyloid ﬁbril formation by stabilizing Aβ protoﬁbrils,” Pro- expression of Aβ(1-42) in wild-type human amyloid protein ceedings of the National Academy of Sciences of the United States precursor transgenic mice: synaptotoxicity without plaque of America, vol. 104, no. 49, pp. 19232–19237, 2007. formation,” Journal of Neuroscience, vol. 20, no. 11, pp. 4050–  D. Dias-Santagata, T. A. Fulga, A. Duttaroy, and M. B. Feany, 4058, 2000. “Oxidative stress mediates tau-induced neurodegeneration in  I. H. Cheng, K. Scearce-Levie, J. Legleiter et al., “Accelerating Drosophila,” Journal of Clinical Investigation, vol. 117, no. 1, amyloid-β ﬁbrillization reduces oligomer levels and functional pp. 236–245, 2007. deﬁcits in Alzheimer disease mouse models,” The Journal of  P.-A. Yeh, J.-Y. Chien, C.-C. Chou et al., “Drosophila notal Biological Chemistry, vol. 282, no. 33, pp. 23818–23828, 2007. bristle as a novel assessment tool for pathogenic study  C. Haass and D. J. Selkoe, “Soluble protein oligomers in of Tau toxicity and screening of therapeutic compounds,” neurodegeneration: lessons from the Alzheimer’s amyloid β- Biochemical and Biophysical Research Communications, vol. peptide,” Nature Reviews Molecular Cell Biology, vol. 8, no. 2, 391, no. 1, pp. 510–516, 2010. pp. 101–112, 2007.  M. Morcos and H. Hutter, “The model Caenorhabditis elegans  D. Schenk, R. Barbour, W. Dunn et al., “Immunization with in diabetes mellitus and Alzheimer’s disease,” Journal of amyloid-β attenuates Alzheimer disease-like pathology in the Alzheimer’s Disease, vol. 16, no. 4, pp. 897–908, 2009. PDAPP mouse,” Nature, vol. 400, no. 6740, pp. 173–177, 1999.  Y. Wu and Y. Luo, “Transgenic C. elegans as a model in  C. Hock,U.Konietzko,J.R.Streﬀer et al., “Antibodies against Alzheimer’s research,” Current Alzheimer Research, vol. 2, no. β-amyloid slow cognitive decline in Alzheimer’s disease,” 1, pp. 37–45, 2005. Neuron, vol. 38, no. 4, pp. 547–554, 2003.  J. J. Sager, Q. Bai, and E. A. Burton, “Transgenic zebraﬁsh  J. Gotz, A. Probst, M. G. Spillantini et al., “Somatodendritic models of neurodegenerative diseases,” Brain Structure and localization and hyperphosphorylation of tau protein in Function, vol. 214, no. 2-3, pp. 285–302, 2010. transgenic mice expressing the longest human brain tau  D. Paquet, B. Schmid, and C. Haass, “Transgenic zebraﬁsh as a isoform,” EMBO Journal, vol. 14, no. 7, pp. 1304–1313, 1995. novel animal model to study tauopathies and other neurode- generative disorders in vivo,” Neurodegenerative Diseases, vol.  J.-P. Brion, G. Tremp, and J.-N. Octave, “Transgenic expres- 7, no. 1–3, pp. 99–102, 2010. sion of the shortest human tau aﬀects its compartmental-  D. Paquet, R. Bhat, A. Sydow et al., “A zebraﬁsh model of ization and its phosphorylation as in the pretangle stage of tauopathy allows in vivo imaging of neuronal cell death and Alzheimer’s disease,” American Journal of Pathology, vol. 154, drug evaluation,” Journal of Clinical Investigation, vol. 119, no. no. 1, pp. 255–270, 1999. 5, pp. 1382–1395, 2009.  T. Ishihara, M. Hong, B. Zhang et al., “Age-dependent  D. Games, D. Adams, R. Alessandrini et al., “Alzheimer-type emergence and progression of a tauopathy in transgenic mice neuropathology in transgenic mice overexpressing V717F β- overexpressing the shortest human tau isoform,” Neuron, vol. amyloid precursor protein,” Nature, vol. 373, no. 6514, pp. 24, no. 3, pp. 751–762, 1999. 523–527, 1995.  K. Spittaels, C. Van den Haute, J. Van Dorpe et al., “Prominent  K. Hsiao, P. Chapman, S. Nilsen et al., “Correlative memory axonopathy in the brain and spinal cord of transgenic mice deﬁcits, Aβ elevation, and amyloid plaques in transgenic overexpressing four-repeat human tau protein,” American mice,” Science, vol. 274, no. 5284, pp. 99–102, 1996. Journal of Pathology, vol. 155, no. 6, pp. 2153–2165, 1999.  J. Gotz, ¨ M. Tolnay, R. Barmettler et al., “Human tau transgenic  A. Probst, M. Tolnay, C. Mistl et al., “Axonopathy and mice: towards an animal model for neuro- and glialﬁbrillary amyotrophy in mice transgenic for human four-repeat tau lesion formation,” Advances in Experimental Medicine and protein,” Acta Neuropathologica, vol. 99, no. 5, pp. 469–481, Biology, vol. 487, pp. 71–83, 2001.  J. Lewis, D. W. Dickson, W.-L. Lin et al., “Enhanced neuroﬁb-  T. Ishihara, B. Zhang, M. Higuchi, Y. Yoshiyama, J. Q. rillary degeneration in transgenic mice expressing mutant tau Trojanowski, and V. M.-Y. Lee, “Age-dependent induction of and APP,” Science, vol. 293, no. 5534, pp. 1487–1491, 2001. congophilic neuroﬁbrillary tau inclusions in tau transgenic  E. D. Roberson, K. Scearce-Levie, J. J. Palop et al., “Reducing mice,” American Journal of Pathology, vol. 158, no. 2, pp. 555– endogenous tau ameliorates amyloid β-induced deﬁcits in an 562, 2001. Alzheimer’s disease mouse model,” Science, vol. 316, no. 5825,  M. Higuchi, T. Ishihara, B. Zhang et al., “Transgenic mouse pp. 750–754, 2007. model of tauopathies with glial pathology and nervous system  E. McGowan, F. Pickford, J. Kim et al., “Aβ42 is essential degeneration,” Neuron, vol. 35, no. 3, pp. 433–446, 2002. for parenchymal and vascular amyloid deposition in mice,”  M. Hasegawa,M.J.Smith,and M. Goedert, “Tau proteins Neuron, vol. 47, no. 2, pp. 191–199, 2005. with FTDP-17 mutations have a reduced ability to promote  F. G. Gervais, D. Xu, G. S. Robertson et al., “Involvement microtubule assembly,” FEBS Letters, vol. 437, no. 3, pp. 207– of caspases in proteolytic cleavage of Alzheimer’s amyloid-β 210, 1998. precursor protein and amyloidogenic Aβ peptide formation,” Cell, vol. 97, no. 3, pp. 395–406, 1999.  J. Lewis, E. McGowan, J. Rockwood et al., “Neuroﬁbrillary  D. C. Lu, S. Rabizadeh, S. Chandra et al., “A second tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L)tau protein,” Nature Genetics, cytotoxic proteolytic peptide derived from amyloid β-protein precursor,” Nature Medicine, vol. 6, no. 4, pp. 397–404, 2000. vol. 25, no. 4, pp. 402–405, 2000. International Journal of Alzheimer’s Disease 11  J. Gotz, ¨ J. R. Streﬀer, D. David et al., “Transgenic ani- overexpressing mice prevents tau hyperphosphorylation and mal models of Alzheimer’s disease and related disorders: neuroﬁbrillary tangle formation, but pre-formed neuroﬁbril- histopathology, behavior and therapy,” Molecular Psychiatry, lary tangles do not revert,” Journal of Neurochemistry, vol. 99, vol. 9, no. 7, pp. 664–683, 2004. no. 6, pp. 1445–1455, 2006.  K. Santacruz, J. Lewis, T. Spires et al., “Medicine: tau  J. Avila and F. Hernandez, ´ “GSK-3 inhibitors for Alzheimer’s suppression in a neurodegenerative mouse model improves disease,” Expert Review of Neurotherapeutics, vol. 7, no. 11, pp. memory function,” Science, vol. 309, no. 5733, pp. 476–481, 1527–1533, 2007.  K. Spittaels, C. Van den Haute, J. Van Dorpe et al., “Glycogen  S. Oddo, A. Caccamo, J. D. Shepherd et al., “Triple-transgenic synthase kinase-3β phosphorylates protein tau and rescues model of Alzheimer’s disease with plaques and tangles: the axonopathy in the central nervous system of human intracellular Aβ and synaptic dysfunction,” Neuron, vol. 39, four-repeat tau transgenic mice,” The Journal of Biological no. 3, pp. 409–421, 2003. Chemistry, vol. 275, no. 52, pp. 41340–41349, 2000.  B. Allen, E. Ingram, M. Takao et al., “Abundant tau ﬁlaments  E. G. de Barreda, M. Per ´ ez, P. G. Ramos et al., “Tau-knockout and nonapoptotic neurodegeneration in transgenic mice mice show reduced GSK3-induced hippocampal degeneration expressing human P301s tau protein,” Journal of Neuroscience, and learning deﬁcits,” Neurobiology of Disease, vol. 37, no. 3, vol. 22, no. 21, pp. 9340–9351, 2002. pp. 622–629, 2010.  Y. Yoshiyama, M. Higuchi, B. Zhang et al., “Synapse loss and  A. de Calignon,L.M.Fox,R.Pitsticketal., “Caspase activation microglial activation precede tangles in a P301S tauopathy precedes and leads to tangles,” Nature, vol. 464, no. 7292, pp. mouse model,” Neuron, vol. 53, no. 3, pp. 337–351, 2007. 1201–1204, 2010.  X. Zhu, H.-G. Lee, G. Perry, and M. A. Smith, “Alzheimer  J. Harvey, “Leptin: the missing link in Alzheimer disease?” disease, the two-hit hypothesis: an update,” Biochimica et Clinical Chemistry, vol. 56, no. 5, pp. 696–697, 2010. Biophysica Acta, vol. 1772, no. 4, pp. 494–502, 2007.  W. Lieb, A. S. Beiser, R. S. Vasan et al., “Association of  A. McShea, H.-G. Lee, R. B. Petersen et al., “Neuronal plasma leptin levels with incident Alzheimer disease and MRI cell cycle re-entry mediates Alzheimer disease-type changes,” measures of brain aging,” Journal of the American Medical Biochimica et Biophysica Acta, vol. 1772, no. 4, pp. 467–472, Association, vol. 302, no. 23, pp. 2565–2572, 2009.  S. J. Greco, S. Sarkar, G. Casadesus et al., “Leptin inhibits  H.-G. Lee, G. Casadesus, A. Nunomura et al., “The neuronal glycogen synthase kinase-3β to prevent tau phosphorylation in expression of MYC causes a neurodegenerative phenotype in neuronal cells,” Neuroscience Letters, vol. 455, no. 3, pp. 191– a novel transgenic mouse,” American Journal of Pathology, vol. 194, 2009. 174, no. 3, pp. 891–897, 2009.  D. C. Fewlass, K. Noboa, F. X. Pi-Sunyer, J. M. Johnston, S.  Y. D. Ke, F. Delerue, A. Gladbach, J. Gotz, ¨ and L. M. Ittner, D. Yan, and N. Tezapsidis, “Obesity-related leptin regulates “Experimental diabetes mellitus exacerbates Tau pathology in Alzheimer’s Aβ,” FASEB Journal, vol. 18, no. 15, pp. 1870– a transgenic mouse model of Alzheimer’s disease,” PLoS ONE, 1878, 2004. vol. 4, no. 11, Article ID e7917, 2009.  S. J. Chamberlain, X.-J. Li, and M. Lalande, “Induced pluripo-  Y.-W. Zhang, S. Liu, X. Zhang et al., “A functional mouse tent stem (iPS) cells as in vitro models of human neurogenetic retroposed gene Rps23r1 reduces Alzheimer’s β-amyloid levels disorders,” Neurogenetics, vol. 9, no. 4, pp. 227–235, 2008. and tau phosphorylation,” Neuron, vol. 64, no. 3, pp. 328–340,  K. Takahashi and S. Yamanaka, “Induction of pluripotent stem cells from mouse embryonic and adult ﬁbroblast cultures by  J. Brownlees, N. G. Irving, J.-P. Brion et al., “Tau phosphoryla- deﬁned factors,” Cell, vol. 126, no. 4, pp. 663–676, 2006. tion in transgenic mice expressing glycogen synthase kinase-  K. Takahashi, K. Tanabe, M. Ohnuki et al., “Induction of 3β transgenes,” NeuroReport, vol. 8, no. 15, pp. 3251–3255, pluripotent stem cells from adult human ﬁbroblasts by deﬁned factors,” Cell, vol. 131, no. 5, pp. 861–872, 2007.  J. J. Lucas, F. Hernandez, ´ P. Go´mez-Ramos,M.A.Moran, ´  J. T. Dimos, K. T. Rodolfa, K. K. Niakan et al., “Induced R. Hen, and J. Avila, “Decreased nuclear β-catenin, tau pluripotent stem cells generated from patients with ALS can hyperphosphorylation and neurodegeneration in GSK-3β be diﬀerentiated into motor neurons,” Science, vol. 321, no. conditional transgenic mice,” EMBO Journal,vol. 20, no.1-2, 5893, pp. 1218–1221, 2008. pp. 27–39, 2001.  I.-H. Park, N. Arora, H. Huo et al., “Disease-speciﬁc induced  A. Yamamoto, J. J. Lucas, and R. Hen, “Reversal of neu- pluripotent stem cells,” Cell, vol. 134, no. 5, pp. 877–886, 2008. ropathology and motor dysfunction in a conditional model of  E. Akesson, J.-H. Piao, E.-B. Samuelsson et al., “Long-term Huntington’s disease,” Cell, vol. 101, no. 1, pp. 57–66, 2000. culture and neuronal survival after intraspinal transplantation  F. Hernandez, ´ J. Borrell, C. Guaza, J. Avila, and J. J. Lucas, of human spinal cord-derived neurospheres,” Physiology and “Spatial learning deﬁcit in transgenic mice that conditionally Behavior, vol. 92, no. 1-2, pp. 60–66, 2007. over-express GSK-3β in the brain but do not form tau ﬁlaments,” Journal of Neurochemistry, vol. 83, no. 6, pp. 1529– 1533, 2002.  T. Engel, F. Hernandez, J. Avila, and J. J. Lucas, “Full reversal of Alzheimer’s disease-like phenotype in a mouse model with conditional overexpression of glycogen synthase kinase-3,” Journal of Neuroscience, vol. 26, no. 19, pp. 5083–5090, 2006.  T. Engel, P. Gon ˜i-Oliver,J.J.Lucas,J.Avila,and F. Hernandez, ´ “Chronic lithium administration to FTDP-17 tau and GSK-3β MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 International Journal of Journal of Immunology Research Endocrinology Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Submit your manuscripts at http://www.hindawi.com BioMed PPAR Research Research International Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Research and Treatment Cellular Longevity Neurology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014
International Journal of Alzheimer's Disease – Hindawi Publishing Corporation
Published: Jul 19, 2010
Access the full text.
Sign up today, get DeepDyve free for 14 days.