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FEBS Letters 583 (2009) 2663–2673

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Minireview Animal models of human amyloidoses: Are transgenic mice worth the time and trouble?

Joel N. Buxbaum *

Department of Molecular and Experimental Medicine, W.M. Keck Center for Autoimmune Diseases, The Scripps Research Institute, 10550 North Torrey Pines Road, Mail Code MEM-230, La Jolla, CA 92037, United States

article info abstract

Article history: The amyloidoses are the prototype gain of toxic function protein misfolding diseases. As such, sev- Received 5 June 2009 eral naturally occurring animal models and their inducible variants provided some of the first Revised 15 July 2009 insights into these disorders of protein aggregation. With greater analytic knowledge and the Accepted 15 July 2009 increasing flexibility of transgenic and gene knockout technology, new models have been generated Available online 20 July 2009 allowing the interrogation of phenomena that have not been approachable in more reductionist sys- Edited by Per Hammarström tems, i.e. behavioral readouts in the neurodegenerative diseases, interactions among organ systems in the transthyretin amyloidoses and taking pre-clinical therapeutic trials beyond cell culture. The current review describes the features of both transgenic and non-transgenic models and discusses Keywords: Amyloidosis issues that appear to be unresolved even when viewed in their organismal context. Transgenic model Ó 2009 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Amyloid A AL amyloid Cystatin c Gelsolin Transthyretin Alzheimer’s disease Serpinopathies Familial dementias

1. Why do we need animal models of protein misfolding plain why an amyloidogenic protein, perhaps present from concep- disorders? tion in roughly the same concentrations, does not form tissue deposits until late in life. Nor can we explain why deposits occur Historically, when it was technically difficult to study human in some tissues and not in others and why in some people and disease in detail, except at the autopsy table, we searched for other not in others. Finally, while it is possible to expose a cell to a poten- means of obtaining useful information and many diseases were tial therapeutic, moving the agent to the clinic usually requires modeled (with more or less fidelity) in animals. High resolution extensive animal testing. Thus good animal models have an impor- imaging, sensitive comprehensive physiologic monitoring capabil- tant place in the investigation of diseases of protein conformation. ity and convenient multiple detailed analyses of plasma and cellu- Protein misfolding disorders come in a variety of flavors. We lar components of the body fluids have allowed us to define many can describe them as genetic or acquired, intra or extracellular, physiologic parameters in living humans regardless of their state of gain of function (GOF) or loss of function (LOF), localized or sys- health. On the molecular level we can study the attributes of fold- temic, with or without morphologically evident aggregates, neuro- ing and misfolding in infinite detail using purified proteins in the degenerative or not. Amyloidosis, the prototypic protein folding test tube in an experimentally convenient time frame. We can disorder (or group of disorders), was noted in the mid-19th century add small molecules, peptides, and vary conditions so that we in autopsy specimens from patients with a diverse set of diseases accelerate or inhibit fibril formation. We can derive mathematical [1]. Each amyloid represented the detectable end product of many models that explain why any given precursor goes from a soluble pathologic processes culminating in a final common pathway of to an insoluble state and determine the precise nature of that state aggregation, fibril formation and tissue deposition, although not in atomic detail. Having done all that it is still not possible to ex- necessarily in that order. Twenty-seven such proteins have been identified as amyloid

* Fax: +1 858 784 8891. precursors in humans (Table 1). Further, in addition to the quanti- E-mail address: [email protected] tatively dominant fibrillar component, all deposits regardless of

0014-5793/$36.00 Ó 2009 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.febslet.2009.07.031 2664 J.N. Buxbaum / FEBS Letters 583 (2009) 2663–2673

Table 1 Amyloid fibril proteins and their precursors in human.a Reprinted from Westermark et al. [120]. Permission pending.

Amyloid Precursor Systemic (S) or localized, Syndrome or involved tissues protein organ restricted (L) AL Immunoglobulin light chain S, L Primary Myeloma-associated AH Immunoglobulin heavy chain S, L Primary Myeloma-associated

Ab2M b2-Microglobulin S Hemodialysis-associated L? Joints ATTR Transthyretin S Familial Senile systemic L? Tenosynovium AA (Apo)serum AA S Secondary, reactive AApoAI Apolipoprotein AI S Familial L Aorta, meniscus AApoAII Apolipoprotein AII S Familial AApoAIV Apolipoprotein AIV S Sporadic, associated with aging AGel Gelsolin S Familial (Finnish) ALys Lysozyme S Familial AFib Fibrinogen a-chain S Familial ACys Cystatin C S Familial ABri ABriPP S Familial dementia, British ADanb ADanPP L Familial dementia, Danish Ab Ab protein precursor (AbPP) L Alzheimer’s disease, aging APrP Prion protein L Spongioform encephalopathies ACal (Pro)calcitonin L C-cell thyroid tumors AIAPP Islet amyloid polypeptidec L Islets of Langerhans Insulinomas AANF Atrial natriuretic factor L Cardiac atria APro Prolactin L Aging pituitary L Prolactinomas AIns Insulin L L Iatrogenic AMed Lactadherin L L Senile aortic, media AKer Kerato-epithelin L L Cornea, familial ALac Lactoferrin L L Cornea AOAAP Odontogenic ameloblast-associated L Odontogenic tumors protein L ASemI Semenogelin I L L Vesicula seminalis ATau Tau L L Alzheimer’s disease, fronto-temporal dementia, aging, other cerebral conditions

a Proteins are listed, when possible, according to relationship. Thus, apolipoproteins are grouped together, as are polypeptide hormones. b ADan comes from the same gene as ABri. c Also called ‘amylin’.

the fibril precursor contain a set of accessory molecules including Senescence Accelerated Mice (SAM) and amyloid-containing insu- serum amyloid P-component (SAP), apolipoprotein E, and the pro- linomas in cats [7]. To the extent that the same or similar condi- teoglycan perlecan. The functions of these three molecules, with tions occur in humans the animal disorders can serve as disease respect to fibril formation, are still obscure [2]. In addition to these models. ‘‘accessory proteins” some deposits, particularly those in the brain (which have been studied in most detail) contain other molecules 2. Murine models of the human amyloidoses which have been hypothesized to either enhance deposition or re- tard the process [3]. 2.1. Amyloidosis A (AA) In the two most common systemic human amyloidoses, i.e. AA and AL, large amounts of precursor protein could be obtained from In humans AA amyloidosis occurs as a consequence of chronic human or animal body fluids and the process of fibril formation inflammation, infectious or non-infectious. It is found in approxi- could be studied in the test tube [4,5]. The development of recom- mately 5% of patients with rheumatoid arthritis, an unknown pro- binant molecular techniques made it possible to obtain large portion of individuals with chronic infections and a significant amounts of pure precursor proteins responsible for most of the proportion of non-Ashkenzi Jews with Familial Mediterranean Fe- clinical amyloid syndromes for in vitro studies of fibrillogenesis. ver and individuals with other genetic abnormalities leading to In addition, incubation of a number of molecules associated with autoinflammatory disorders related to the innate immune system neurodegenerative diseases, under amyloid fibril forming condi- [8]. tions in vitro revealed that they too behaved as did classical amy- With respect to the human systemic disorders, the inflamma- loid precursors under the same conditions [6]. Subsequently the tion inducible murine AA model in which susceptible strains of family of amyloid precursors was expanded to include all those mice were exposed to a variety of inflammatory stimuli (subcuta- proteins that formed fibrillar aggregates with the characteristic neous injections of casein, Freund’s adjuvant, turpentine, silver ni- b-sheet structure and dye-binding properties found in the original trate) had been studied long before recombinant proteins became extracellular disorders in vivo and in vitro. available [9]. The isolated fibril was the first non-immunoglobulin There have been numerous studies on naturally occurring and characterized chemically, thus named Amyloid ‘‘A” [10]. The model inducible animal amyloidoses including amyloid A in a variety of provided insight regarding the nature of the precursor, i.e. the ser- species, scrapie in sheep, BSE in cattle, ApoAII isomorphs in the um acute phase apolipoprotein SAA, and the role of inflammatory J.N. Buxbaum / FEBS Letters 583 (2009) 2663–2673 2665 cytokines (IL6, IL1 and TNFa) in stimulating SAA production via quency of amyloid deposition with age had been previously noted NFjB, with the subsequent generation of AA as the direct fibril in human autopsies [26]. The amyloid consisted of intact apolipo- forming precursor by proteolysis of SAA, apparently by macro- protein AII [27]. Mouse strains bearing the amino acid glutamine at phage proteases [11–14]. The model suggested that genetically position 5 (ApoA2c) were found to be susceptible to this form of controlled differences in precursor structure could determine indi- amyloidosis, while strains having proline in the same position vidual susceptibility to amyloid deposition in response to a chronic (ApoA2a or 2b) were not [28]. The potential for amyloidogenesis inflammatory stimulus. It also served as a test system for mole- could be transferred to a non-amyloid forming strain by making cules designed to inhibit tissue deposition by interfering with the it congenic for the amyloidogenic isoform [29]. While AA deposi- interaction between AA aggregates and matrix proteins that were tion was also found with aging in some strains of mice and some subsequently evaluated in human clinical trials [15,16]. mice had both forms, there did not appear to be cross-seeding in The murine AA model has also raised the issue of whether the naturally occurring diseases. However, subsequent experi- ‘‘infectivity” plays a role in other forms of amyloidosis in addition ments in which fibrils or fibril fragments were injected into ani- to the prionoses. It has been shown in many laboratories that injec- mals representing each model suggested either an additive or tion of sonicated splenic extracts from mice with AA deposition, reciprocal relationship in the two forms of fibril deposition [30]. when given in conjunction with an inflammatory stimulus, will These results, while interesting and suggesting that cross-seeding accelerate the appearance of amyloid fibrils in a naïve recipient can be induced experimentally, are not consistent with cross-seed- from weeks to days [17]. The active component (originally known ing in the natural course of either AA or ApoAII deposition in mice. as amyloid enhancing factor or AEF), which appears to serve as a As in the AA model, injection or feeding of ApoAII fibril fragments seed, is the growing end of the fragmented fibrils. Amyloid A was could accelerate deposition [31]. The ApoAII amyloid could also be the first form of systemic amyloidosis to display the seeding phe- transmitted by fecal ingestion or vertically during nursing [32]. nomenon in vivo. Tissue deposition can also be accelerated by Hence the phenomenology of acceleration by seeds was similar the injection of fibril fragments from a variety of sources including to that seen in the AA model. fragmented fibrils formed from transthyretin peptides, silk, and Many, but not all, amyloid precursors form fibrils in a process of bacterial curlin protein as well as AA fibrils themselves [18].It nucleated polymerization [33]. Addition of small amounts of fibril has also been established that oral ingestion of such seeds may fragments (seeds) to the in vitro reaction accelerates the process of serve as accelerants [19,20]. In principle this is felt to differ from fibrillogenesis [34]. It has been assumed that the association of var- the infectivity of the true prion disorders, since in the case of pri- ious forms of amyloidosis with aging reflects a latent period during ons, the animals would not get aggregation and deposition if they which the seeds form. The seeding experiments in the AA and Apo- did not see the scrapie conformer or a similar seed. Hence, there AII models do not necessarily support this argument. In both these may be a meaningful distinction between initiation (as seen in systems the precursor (SAA or ApoAII) is present in very high the prionoses) and acceleration as seen with AEF and murine Apo- concentrations either as the result of inflammation (SAA) or in AII (see below). response to diet ApoAII [35]. Both precursor molecules are apo- Transgenic technology has not played a major role in the inves- lipoproteins, hence have a sufficient degree of hydrophobicity to tigation of AA disease. However, three sets of transgenic studies be potentially unstable in aqueous media. Both are amyloidogenic have been informative in the investigation of AA pathogenesis. Re- when freed from their HDL ligand. SAA requires cleavage to gener- cently, it has been shown that, as expected, IL-6 transgenics will ate the structure that has optimal fibril forming capacity. Inflam- develop AA amyloid deposition on the basis of increased SAA syn- matory cells provide both a cellular source of appropriate thesis and processing and such animals can be utilized in testing protease activity as well as the amyloidogenic substrate. These ap- for factors which accelerate the process [21]. pear to be special cases, peculiar (but not exclusive) to the mouse. In a second transgenic study over-expression of the gene encod- The relatively high frequency of these conditions in particular ing heparanase revealed that shortening the length of the heparan mouse strains and their relative rarity in humans may make them sulfate chains in matrix proteoglycans made animals resistant to less informative as models of human disease than interesting AA deposition [22]. In other AA related studies gene silencing has experimental systems in their own right. been utilized to investigate the role of serum amyloid P-compo- nent (SAP), the murine acute phase protein found in all amyloid 2.3. Prion diseases deposits, in the pathogenesis of AA amyloidosis in mice. Two inde- pendent studies of separately derived strains in which its gene The same can be said of the prionoses. Although the apparent (APCs) was silenced by targeted disruption, showed that inflamma- epidemic of variant Jakob-Creuzfeldt disease associated with the tion-induced AA occurred at a moderately decreased rate relative ingestion of beef from animals with Bovine Spongioform Encepha- to controls, and that the rate of absorption of the deposits after lopathy (BSE or ‘‘mad cow disease”) and its genetic counterpart stopping the stimulus was no different in the SAP knockouts and (CJD) indicate that there is a human homolog [36]. Here again controls. Thus, despite being present in the deposits of all forms much of the characterization of murine and hamster scrapie was of amyloid, SAP was not required for either fibril deposition or sta- achieved well before the availability of transgenic animals. The no- bility in vivo [23,24]. One can envision experiments in which a tion of ‘‘protein only infectivity” mediated by templated misfolding gene or genes encoding the protease(s) required for the processing of a native protein was a novel idea, which appears to be generally of the SAA precursor to AA might be silenced with a profound ef- correct [37]. Exposure via ingestion followed by transport to the fect on the deposition phenotype. However, such experiments have brain through lymphatics and a long incubation period is well not been reported. established although we are still far from full understanding of the process. The demonstration of strain differences related to spe- 2.2. Apolipoprotein AII cific protein structures and the variability of such structures in a gi- ven strain is under active investigation as is the basis for strain A second naturally occurring animal amyloidosis was described differences in pathogenetic effects, i.e. more amyloid fibril forma- by Japanese investigators who, in the course of breeding sub- tion in some strains and more spongioform change in others strains of AKR mice to select for longevity, discovered that several [38]. As in many of the pathogenic amyloidoses there is accumulat- of their variant strains uniformly developed amyloid deposition ing evidence that the mature fibrils are not the toxic element late in life [25]. This was not surprising since the increasing fre- rather it is oligomeric pre-fibrillar species that are the major path- 2666 J.N. Buxbaum / FEBS Letters 583 (2009) 2663–2673 ogenetic species. These data are quite convincing in tissue culture potentially interactive proteins are silenced (see above re:SAP but in vivo confirmation remains an investigative goal. knockouts). Apolipoprotein E knockouts have been informative, Transgenic/knockout animals enabled the performance of the although not consistent, in studies of pathogenesis in Alzheimer’s critical experiments demonstrating that host specificity was a disease (AD) models [43]. Animal models lend themselves to test- function of the endogenous PrPc gene since murine PrPsc was not ing the roles of diet and other environmental factors on disease pathogenic in mice in the absence of a functional PrPc gene [39]. development in the presence of a bona fide precursor transgene. Similarly the demonstration that BSE aggregates could affect mice The most obvious use is in the evaluation of therapies using both in which the endogenous PrPc had been replaced by its human small molecule and biologic approaches to prevention and homolog was the best laboratory evidence for transmission of that treatment. agent into humans [36]. What properties would we like in such models? Ideally one would like the precursor to be driven by its endogenous promoter 2.4. AL amyloidosis so that its tissue expression reflects what occurs in vivo with re- spect to known physiologic and environmental influences (so- Transgenesis technology and its gene silencing variant have al- called ‘‘construct validity”). It would be preferable to have the gene lowed the development of a number of potentially relevant models expressed at levels similar to those seen in vivo, usually achieved of human protein misfolding diseases but have not been fruitful for by integration of a single functional gene copy or the diploid state some human amyloidoses. For instance there have been numerous in a homozygous cross. This becomes particularly important in attempts to generate a transgenic model of the systemic amyloido- models in which a therapeutic is designed to bind to the precursor sis related to immunoglobulin light chain deposition (AL). No suc- with a defined stoichiometry. Multiple copy number models might cessful models have been reported, nor has the reason for the lack require much more drug for effect than would be necessary in pa- of success been defined, although it may be that the amyloidogenic tients in whom there may be only one or at most two genes encod- potential of a particular light chain structure can only be realized ing the amyloidogenic protein. Thus an agent that might be when the protein is synthesized and secreted to a level equal to effective in patients might be ineffective or toxic in a model that or greater than the critical concentration required for its aggrega- depended on overproduction of the amyloid precursor to obtain tion under physiologic conditions. In vivo this may require a degree the disease phenotype simply because there is too much precursor of clonal expansion that has not yet been achieved experimentally. (lack of ‘‘predictive validity”). Transfection of the murine hybridoma parent cell line SP2 with One would also like the model to display both clinical and path- an amyloidogenic human light chain and injection of the cells into ologic phenotypes that resemble those seen in human patients a recipient animal was not experimentally useful since the SP2 with the disease being modeled, including its temporal pattern of cells grew too quickly to allow any analysis of the process of amy- development, i.e. more disease with increasing age in the case of loid formation or deposition even if it had occurred. the age dependent amyloidoses and tissue distribution of deposits The only model, which has had some success, is highly artificial (‘‘face validity”). Once it is established that the model reflects the and involves injecting large amounts of an amyloidogenic precur- human disorder one would like to be able to accelerate its develop- sor light chain either intraperitoneally or under the skin [40].A ment (without changing the responsible molecular events) so data mass forms consisting largely of fibrillar material surrounded by could be acquired in a more compressed time frame. macrophages and neutrophils which is ultimately resorbed. The For some models, while mice offer the advantage of extensive host response to the mass suggested that an antibody directed to- knowledge of their genetics, their small size makes certain types ward epitopes available on the aggregates might enhance the of manipulations and studies difficult. Some laboratories have cho- inflammatory response and hasten clearing. This is a cumbersome sen to develop transgenic rat models for conditions in which these model that has little resemblance to the development of the dis- issues (e.g. organ transplantation therapies) are serious consider- ease in vivo. Nonetheless anti-amyloid antibodies have been gen- ations [44]. In other circumstances lentiviral or adenovirus associ- erated that accelerate clearing of the deposits and have been ated viral vectors encoding amyloidogenic alleles have been humanized for use in clinical trials [41]. injected intracerebrally under stereotactic control to target specific brain regions. These methods are easier in rats but have now been 2.5. Transgenic considerations adapted to mouse studies as well. In addition the larger rat brains allow more informative use of imaging technology. What kind of information would emerge from transgenic dis- For impatient investigators the introduction of amyloid precur- ease models that might be more difficult or impossible to obtain sors into worms (Caenorhabditis elegans) and flies (Drosophila mel- in other experimental systems? Since the extracellular amyloidos- anogaster) compresses the time necessary to obtain a disease es are systemic, with deposition frequently taking place at location phenotype [45,46]. However, the relationship between that cellu- distant from the site of synthesis an organismal rather than tissue lar and molecular phenotype and human disease may be problem- culture approach would seem to be favored. Models should allow atic. On the other hand the comparability of these post-mitiotic the development of more precise notions of pathogenesis and the model systems to mammalian post-mitotic tissues, such as neu- roles of proteins other than the actual precursor in facilitating or rons or myocytes, suggests that the molecular aspects of some of inhibiting amyloid generation and deposition. In the most sophis- the models may be extremely useful in the analysis of those disor- ticated instances, gene replacement (knock in) technology allows ders in more long-lived species. This has been evident in a series of the replacement of a precursor molecule with a gene or exon experiments in worms transgenic for a gene encoding a form of the encoding an amyloidogenic sequence that differs from the original. Huntington disease protein with a poly-Q region containing a This approach has been utilized to demonstrate the requirement stretch of glutamines that does not normally aggregate. By silenc- for Cys10 in the V30 M TTR structure in order to achieve aggrega- ing genes encoding various components presumed to be involved tion and deposition in V30 M TTR transgenic animals [42]. Such in the handling of misfolded proteins the threshold for aggregation experiments validate data obtained in vitro on the effects of spe- is lowered and the pathologic phenotype appears [47]. While this cific structural changes on the process of fibril formation. may not be an accurate ‘‘disease model” it allows detailed investi- The effects of genetic factors, not readily apparent in the human gation of cellular and molecular pathogenesis and could be used as diseases, in vitro or in tissue culture settings, can be assessed in an in vivo screen for inhibitors that might be useful in the analo- transgenic animals, particularly in crosses in which genes encoding gous human disorders. J.N. Buxbaum / FEBS Letters 583 (2009) 2663–2673 2667

At this moment none of the murine transgenic models of any of at an earlier age than the Congophilic deposits. The occurrence of the systemic amyloidoses exhibit ideal characteristics. While some fibrillar deposits seems to be both a function of TTR concentration of the variation reflects general differences between humans and and age (duration of exposure) a phenomenon that was subse- mice (the details of which are not fully understood), some are a quently confirmed in the human disease when non-fibrillar TTR consequence of particular features of murine molecules and their deposits were found in the peripheral nerves of Portuguese pa- interaction with transgene products [48]. tients with early FAP [56]. The age and gender dependent deposition of the wild-type pro- 2.6. The transthyretin (TTR) amyloidoses tein resembles that seen in the human SSA disorder. Transcription analyses of these animals indicated that cardiac deposition oc- There are three human disorders characterized by the extracel- curred when the liver did not respond to the presence of the many lular deposition of TTR aggregates, Familial Amyloidotic Polyneu- copies of wild-type TTR with an unfolded protein response (UPR) ropathy (FAP), Familial Amyloidotic Cardiomyopathy (FAC) and and subsequent transcription of chaperone genes and elements Senile Systemic Amyloidosis (SSA). The first two are caused by of the ubiquitin-proteasome system (Buxbaum et al., unpublished). mutations. The last is the result of age dependent cardiac deposi- In animals with such a transcriptional response histologic cardiac tion of the wild-type protein. In each case the homo-tetramer re- deposition did not occur and no oxidative stress response was seen leases a monomer subunit, which misfolds and is subject to in the hearts. On the other hand, livers from animals with cardiac aggregation and tissue deposition in its target organ [49]. What deposits showed no UPR or chaperone response while their hearts determines the site of deposition of any of these proteins is still showed an exuberant transcriptionally mediated oxidative stress unknown. response. At this time it is unknown whether the tissue responses The original TTR transgenics utilized cDNA’s encoding the amy- will be the same to the normal concentration of a thermodynami- loidogenic allele V30 M TTR driven by the relatively promiscuous cally unstable TTR as they are to large amounts of the wild-type metallothionein promoter. The animals showed early deposition protein. If the absolute amounts of misfolded TTR are equivalent, in all tissues in which the mRNA was identified, however in tissues representing a relatively large proportion of the total amount of other than the liver and choroid plexus there was no expression of the unstable protein and a small proportion of the wild-type mol- the endogenous TTR gene, suggesting that such a construct would ecule, the processes should be similar. This remains to be proven not generate a useful disease model since it was being expressed in experimentally. tissues not normally synthesizing the protein [50]. The animals did The strain derived from the mutant L55P TTR gene contained a not develop peripheral neuropathy, the hallmark of the human dis- single copy of the gene and showed no deposition phenotype even ease. Subsequently the intact human gene with most of its known at 2 years of age in animals homozygous for the human construct. regulatory sequences was reconstructed from two partial genomic Inoculation of these animals with fibrils made from TTR peptides clones isolated from a human EcoR1 library made from an FAP pa- that behaved as active AEF in the inflammation-induced AA model tient and used to generate several additional transgenic strains did not result in the development of TTR deposits in these mice [51]. One of these contained 6.0 kb of sequence upstream of the [57,58]. In subsequent studies the mutation was crossed onto the initiation site, which showed appropriate tissue specific expression murine TTR knockout background. One-third of those animals and tissue deposition (gut, heart, skin, and kidney) beginning at showed deposition suggesting that the murine TTR molecule inhib- about 1 year of age. These animals contained 30–60 copies of the ited the aggregation and deposition of the highly unstable human human gene, but still did not display peripheral or autonomic neu- molecule [59]. Combined in vivo and in vitro studies subsequently ropathy. Nonetheless they were considered moderately successful. showed that in the presence of the murine TTR gene, highly stable The role of environment had to be addressed when these trans- human-mouse hetero-tetramers were formed, thus reducing the genics were moved from a conventional animal facility to a specific availability of the free human monomer precursor of the aggre- pathogen free facility. With that move the mice stopped develop- gates [48]. Further experiments showed that administration of ing tissue deposits to the same extent as previously [52]. As ex- diflunisal, a molecule that binds in the thyroxine binding pocket pected they showed a difference in the gastrointestinal flora in of TTR and is currently in clinical trials in patients with FAP, stabi- the two locales and hypothesized that some degree of inflamma- lized the human L55P molecule to denaturation by urea to the tion was required to stimulate the formation of tissue aggregates same extent as did the murine protein in a fashion similar to that [53]. On the surface this explanation seems unlikely since hepatic seen when Portuguese V30 M TTR carriers also bear the T119 M TTR synthesis, which is responsible for producing the bulk of circu- TTR allele in trans [60]. lating TTR, the fibril precursor, is down-regulated in the course of Other investigators have used the L55P allele in different molec- inflammation by the action of inflammatory cytokines [54].Itis ular settings to accelerate pathogenesis. When the animals were also not clear whether genetic drift has been completely elimi- crossed with HSF1 knockout mice that were unable to mount a nated as a proximal or contributory cause. Other TTR transgenics chaperone response, the offspring showed relatively early gastro- in other laboratories have yielded perfectly valid phenotypes when intestinal deposits and, for the first time, deposits in sciatic nerve reared under SPF conditions. and dorsal root ganglia [61]. The demonstration that silencing a Transgenics made from the wild-type and mutant TTR genes of critical transcriptional regulator of the unfolded protein response an individual carrying the highly unstable L55P TTR mutation pro- accelerated disease confirmed its involvement in protection vided several interesting insights into the nature of transgenic ani- against tissue damage produced by TTR aggregates. What is not mal models. Both genes used to produce the transgenics were clear from these studies is whether the absence of HSF1 is making cloned as 19.2 kb genomic fragments containing all the known reg- target cells more sensitive to toxicity of extracellular aggregates, ulatory sequences of the normal TTR gene [55]. Animals bearing whether its impact is on the liver’s capacity to adequately chaper- the wild-type gene contained 100 copies and displayed amyloid one misfolded TTR synthesized in the hepatocyte or whether TTR is deposition in the kidneys (80%) and the hearts (50%) after being made in dorsal root ganglia and the absence of HSF1 results 18 months. Both strains showed tissue expression in the pattern in cell death based on aggregation of locally synthesized TTR? expected from studies in humans, i.e. liver, choroid plexus, eye, A transgenic strain has also been constructed using the gene gut and kidney. In the animals bearing the wild-type gene, males encoding I84S TTR, a very interesting mutation in which the TTR showed greater deposition than the females. In both sexes younger retinol binding protein interaction site is disrupted. Neither amy- animals showed non-amyloid (diffuse) deposits in the same organs loid nor diffuse TTR deposits have been seen in these animals over 2668 J.N. Buxbaum / FEBS Letters 583 (2009) 2663–2673 many generations, even when crossed onto the murine TTR knock- As a disease model these animals have validated the notion of out background [62]. These animals appear to carry 8–10 copies of IAPP amyloidosis as playing a role in the pathogenesis of type II the human gene. They have been used as a model system in which diabetes. While relative or absolute insulin insufficiency may be to test the efficacy of TTR anti-sense to specifically silence tran- primary the subsequent insulin resistance stimulates the co- scription of the mutant allele [63]. Since these animals have no expression of the IAPP and insulin genes. In these models the mag- deposition phenotype the effect of such silencing on deposition nitude and cell site of that expression was insured by driving the cannot be judged. Successful silencing would provide proof of prin- IAPP construct with an insulin promoter. Since it has been shown ciple of the approach to show that production of the protein can be in vitro that insulin as well as rat and presumably mouse IAPP in- diminished in the liver. hibit human IAPP fibril formation (chaperone) perhaps it is the rel- Thus it is quite clear that murine transgenic models of the TTR ative amount of each set of molecules that determines the rate and amyloidoses have provided interesting insights into the pathogen- extent of oligomerization and fibril formation and accounts for the esis of the human disorders which they were generated to model. variability among the different transgenic strains. One of the vari- However, the necessity for over-expression to overcome the stabil- ables in disease development might be the presence of mixed hu- ity of murine-human hetero-tetramers and the apparent differen- man/rodent IAPP aggregates that are less fibrillogenic than homo- tial processing of misfolded-prone proteins between humans and IAPP complexes in a fashion similar to that seen with human/mur- mice or the need to cross the animals onto mice that have deletions ine TTR hetero-tetramers. These models continue to be explored in genes with major homeostatic functions other than simply chap- with the notion that stabilizing IAPP will reduce the rate of b-cell eroning the amyloid precursor, have made them less than optimal loss and make molecules that enhance insulin production and re- tools for either fine analysis or experimental therapies. There have lease or reduce peripheral insulin resistance more effective, thus been recent successful efforts to ‘‘knock in” human TTR transgenes increasing the effectiveness of treatment. into the murine TTR locus [64]. It remains to be seen whether experiments with these strains can overcome the experimental 2.8. Gelsolin disadvantages of the earlier models. Gelsolin is the precursor protein in the Finnish form of Familial 2.7. Islet amyloid polypeptide (Amylin, IAPP) Amyloidotic Polyneuropathy, which is associated with skin, facial nerve, cardiac and renal amyloid deposition [77]. It represents an- Homogeneous eosinophilic deposits were first described in the other variation on the theme of systemic amyloidosis. In this in- pancreas at autopsy of diabetic humans in 1901. Their amyloid nat- stance synthesis and deposition of the precursor occurs at ure and association with aging in diabetics taking insulin was multiple sites. In the human disorder a mutation at position established in autopsy series much later and the identification of D187 to N or Y (D187 N/Y) in plasma gelsolin compromises the fibril as IAPP or amylin almost simultaneously by two laborato- Ca2+-binding in domain 2 enabling aberrant cleavage by furin gen- ries in the mid-1980s [65,66]. This is a localized form of amyloid erating a secreted 68 kDa fragment (C68) that can be further with systemic effects thus is probably best studied in an organis- cleaved in the extracellular space by a type I matrix metallopro- mal context. Comparative structural studies showed that the ami- tease, such as MT1-MMP, to generate the major (8 kDa) and minor no acid residues 20–29 were critical for the amyloidogenicity of (5 kDa) amyloidogenic fragments that deposit in the tissues [78]. the 37 amino acid mature peptide. Proline at position 28, the res- A single transgenic strain has been reported in which the mutant idue found in mouse, rat and hamster, was anti-amyloidogenic gelsolin has been expressed in C57Bl/6 mice under the control of a [67]. This observation prompted several laboratories to create creatine kinase promoter in the context of a 50 globin intron and a transgenic mouse lines, correctly assuming that there would be bovine growth hormone poly A site (Page et al., PNAS, USA, in no endogenous IAPP amyloidogenesis to confuse the interpretation press). of the data. As expected, because of the promoter choice, gelsolin synthesis Since it had previously been established that insulin and IAPP was seen only in cardiac and skeletal muscle. Congophilic gelsolin were co-expressed and secreted by the pancreatic b-cell each lab- deposits were found in capillaries and the skeletal muscle endo- oratory used some form of the rat insulin promoter to drive human mysium. Deposition increased with age. The model appears to IAPP cDNA [68–71]. In some laboratories intron fillers derived from faithfully reproduce the molecular events resulting in the same either globin or albumin were used with the purpose of enhancing amyloidogenic fragments seen in the human disease but results functionality of the transgene. The number of integrated copies of in both extra and intracellular aggregates rather than only the the human construct was not specifically noted in any of the re- extracellular deposits described in human gelsolin amyloidosis. ports. Strain backgrounds varied with FVB/N, C57Bl/6 and C57Bl/ Pathologically vascular disease is less prominent and the muscle 6 DBA/2 all being used as hosts, with subsequent crosses onto lesions of the animals appeared to be more like inclusion body a variety of backgrounds to determine the effects of other genes myositis, a sporadic muscle disease of the elderly in which a vari- (e.g. ApoE, Agouti, Ob/Ob) [72,73]. The endpoints for all were in- ety of fibrillogenic proteins have been found to be deposited, the creased IAPP concentrations in the serum, human IAPP staining most prominently described of which has been Ab [79]. in b-cells, pancreatic amyloid deposition with fibrils derived from human IAPP and hyperglycemia or overt diabetes. Beta cell IAPP 2.9. Alpha-1-anti-trypsin (AAT) (Z-variant) deficiency synthesis was shown in some of the transgenic animals in virtually all the experiments. Increased serum IAPP was also frequent. How- While not originally recognized as a protein misfolding disorder ever, in only one model did pancreatic amyloid develop without and certainly not having any of the characteristics of the systemic further experimental manipulation [70]. It was ultimately estab- amyloidoses, i.e. Congophilic extracellular deposition at locales lished that procedures that increased insulin resistance (glucocor- distant from the site of synthesis, homozygous AAT deficiency ticoids, high fat diets, mating with obesity predisposed strains) all has the characteristics of both an LOF and GOF mutation [80]. increased the frequency of pancreatic amyloid deposition, b-cell The affecteds have diminished levels of a specific circulating serpin loss and hyperglycemia [74,75]. More refined analyses have sug- (serine protease inhibitor), exhibit recurrent pulmonary disease gested that non-fibrillar aggregates were cytotoxic, in some mod- and ultimate respiratory failure because of excessive neutrophil els inducing b-cell loss prior to significant formation of mature elastase activity in the lungs causing destruction of lung tissue. It amyloid deposits [76]. is an LOF disorder and belongs to the class of serpinopathies. J.N. Buxbaum / FEBS Letters 583 (2009) 2663–2673 2669

The mechanism of aggregation in the serpinopathies is quite gene copy number. It is not clear why over-expression is required different from that in the amyloidoses. The effect of the mutation in many or all of these models. It is possible that murine cells, par- is to interfere with the generation of the active site in which the ticularly neurons, are better equipped to chaperone or dispose of target protease must fit allowing insertion of the domain of misfolded proteins than human cells of similar lineages, although another AAT molecule to form a dimer with subsequent homo- there are no quantitative data addressing this question. polymer propagation. A similar mechanism has been proposed Lesson number 3: Genetic background makes a difference. The for neuroserpin in the dementia familial encephalopathy with same mutation carried in different mouse strains may show sub- inclusion bodies (see below). stantial variation in phenotype, from no disease to early death in The Z-variant is one of the few examples of intracellular aggre- some cases [97]. This should not be surprising since humans are gation of a protein normally secreted by hepatocytes, since the li- not inbred (for the most part) and could be used to an advantage ver cell seems to be particularly well-suited to deal with in understanding the pathology by mapping the responsible con- potentially misfolded proteins, e.g. TTR mutants. The AAT liver dis- tributory loci. The corollary from human genetics is that ‘‘there plays intracellular inclusions, hepatocyte loss, fibrosis and an in- are no single gene diseases”. For instance Familial Amyloidotic Pol- creased frequency of hepatocarcinoma. All of these features have yneuropathy (FAP) caused by the V30M TTR mutation behaves as been recapitulated in the transgenic models of the disease an autosomal dominant disease (see above). Yet the penetrance [81,82]. Further it has been possible to treat these animals with is similar in Japanese and Portuguese carriers but far less so in small molecules that behave like molecular chaperones [83]. Swedes with the same mutation [98]. Even within the Portuguese population the age of onset of disease can vary dependent on 2.10. Neurodegenerative protein misfolding diseases which parent contributes the mutant allele as well as genetic var- iation at other loci that may be involved in pathogenesis [99,100]. We have characterized the neurodegenerative protein misfold- Lesson number 4: Environment matters. Variation in phenotype ing diseases as extrinsic, i.e. the prionoses, or intrinsic, i.e. indepen- from laboratory to laboratory reflecting differences in diet, hus- dent of external agents. The latter constitute the majority of the bandry, maintenance and factors that have not yet been elucidated described disorders. In these diseases the precursor is synthesized can all impact on disease expression and the potential validity of and misfolds either within or in proximity to the target of its tox- the model [52,101,102]. icity. Conceptually these disorders should be readily approachable Lastly is the element of publication bias, i.e. the published pa- using tissue culture techniques rather than requiring animal mod- pers are much more likely to document successfully generated els, since all the action is taking place in a confined space. The util- transgenic strains than those in which no phenotype was obtained. ity of animal models relates to two features of most of these disorders. To some extent they are all age dependent, a quality dif- 2.12. Cystatin C (cerebral amyloid angiopathy) or hereditary cerebral ficult to establish in tissue culture. Further, it is desirable to ulti- hemorrhage with amyloidosis, Icelandic type (HCHWA-II) mately validate any molecular observation with a behavioral readout. Thus a variety of animal models of Alzheimer’s disease, Many of the human amyloidoses affect blood vessels. In this Parkinson’s disease, Huntington’s disease, Tauopathies, ALS have condition a mutation in Cystatin C, a cysteine protease inhibitor, been generated and extensively employed in a variety of settings Leu68Gln, causes it to dimerize by a process thought to involve do- and have been the subjects of many excellent reviews [84–89]. main swapping followed by aggregation within the walls of cere- bral blood vessels [103]. The aggregation is associated with 2.11. Alzheimer’s disease (AD) multiple cerebral hemorrhages in the carriers. However, mice made transgenic for the human mutant allele with significant In many ways the attempts to make useful murine transgenic over-expression did not display Congophilic angiopathy [104]. models of human AD although imperfect, have been among the Immunohistochemical analysis of AD brains has shown the most informative. Over the last several years there have been presence of cystatin C in both plaques and cerebral vessels. When excellent detailed reviews of these models to which the reader wild-type cystatin mice were crossed with the APP23 AD model can refer for specific information [90–93]. I will not review them mice there was a 50% reduction in cortical plaques, a 50% reduction here except to draw general lessons, some of which have been dis- in Ab1–40 and a 25% reduction in Ab1–42 concentrations in the brain cussed with respect to the systemic amyloidoses in earlier sections. at age 14.5 months. Similar effects were seen when the cystatin C Lesson number 1: mice are not humans. We should not expect animals were crossed with the TG2576 AD model mice. These the expression of a human disease-associated gene in a mouse to experiments are consistent with in vitro experiments showing precisely duplicate the human disease of interest. For instance, direct binding of cystatin C to Ab1–40 and Ab1–42 with inhibition while Tau phosphorylation has been seen in some transgenics of fibril formation [104]. bearing either a mutant Ab gene or a combination of mutant Ab and mutant presenilin 1 (PS-1) genes, neurofibrillary tangles (a 2.13. BRI2 related dementias characteristic feature of human AD) are only seen consistently in the triple transgenics that also carry a Tau mutation [94–96]. Mutations in the BRI2 gene have been identified in familial Brit- Few studies have been directed at examining differences between ish Demential and familial Danish dementia [105,106]. A point mice and humans with respect to defining systematic guidelines mutation (FBD) and a decamer duplication (FDD) allow read applicable to all or most transgenic models. through the normal stop codon to yield a protein 11 amino acids Lesson number 2: Phenotypes produced by insertion of a trans- longer than in the native type II transmembrane protein. Furin type gene encoding a GOF protein are quantitatively much more dose- proteolysis generates a 34 amino acid fibril precursor which forms dependent than models in which a gene deletion was generated Congophilic vascular deposits (Congophilic angiopathy) ‘‘soft” to reflect a LOF disorder. While homozygous gene deletions may parenchymal plaques and fibrillar deposits in the brains of the car- be embryonic lethal and hemizygotes give a survival disease phe- riers. Attempts to generate a transgenic model for FBD were not notype in ‘‘LOF” models, the number of copies of a transgene successful [107]. However, transgenic animals produced by using encoding a GOF protein can determine whether the disease pheno- a cDNA enoding the Danish BRI2 extended sequence driven by type is penetrant in the model, its temporal development and its the murine prion protein promoter injected into C3HeB/FeJ severity, since in general the level of protein production parallels oocytes, subsequently bred into C57Bl/6 for 10 generations, 2670 J.N. Buxbaum / FEBS Letters 583 (2009) 2663–2673 developed Congophilic angiopathy at 7 months of age. Punctate with similar proteins in a manner that allows both to assume (or and diffuse antibody positive deposits and gliosis were seen in re-achieve) native stable conformations. Are the effects in the the regions of the deposits [108]. transgenic models only properties of these relatively artificial sys- When Adenovirus Associated Viral vectors containing se- tems or do they reflect in vivo interactions that play a role in the quences encoding the BRi2 protein were injected intracerebrally pathogenesis of human AD? Obviously these observations could into AD model mice the neuropathologic features of AD were sup- not have been made in the absence of animal models of AD. In or- pressed [109]. These studies were consistent with in vitro experi- der to fully establish these phenomena as relevant for these and ments showing that BRI2 bound to amyloid b precursor protein other proteins it would seem that an in vitro interaction must be interfering with its processing by secretases [110,111]. Hence like observed with recombinant forms of the proteins with reasonable cystatin C, the wild-type form of the amyloidogenic precursor stoichiometry. Inhibition of fibril formation should be clear. interferes with molecular events involved in AD pathogenesis. Expression of a transgene encoding the putatively interacting pro- tein should impact on the pathology and physiology of the model 2.14. Familial encephalopathy with neuroserpin inclusion bodies disease and silencing of the endogenous gene should have the (FENIB) opposite effect on the disease phenotype. All should be confirmed in more than one laboratory. Lastly, or perhaps firstly, there should In 1996 a kindred was reported with dementia beginning in be some evidence that there is a relationship of the protein in ques- their 40’s, apparent autosomal dominant inheritance and the strik- tion to the human disease. To date this has only been achieved for ing appearance of neuronal inclusion bodies in the cortex and else- the interaction between TTR and Ab. where [112]. The inclusions were unique (Collins bodies) and were found to be composed of aggregates of the serine protease tissue 3. Coda: are the models worth the time and trouble? plasminogen activator inhibitor neuroserpin. Mutations in the gene were identified in independent kindreds (P112, S52R, S49P). Each animal model is akin to a single patient. To the extent that The wild-type gene was subsequently identified immunohisto- we can examine the organismal effects of what may be a single chemically in AD plaques. In vitro incubation of the wild-type pro- mutation in a single protein they are useful. Whether they can pro- tein with amyloidogenic Ab peptides inhibited fibril formation and vide the same mechanistic insights as cultured cells of the appro- their cytotoxic effect on PC 12 cells [113]. priate lineage is less certain for many of the disorders. They Transgenic flies were generated using the wild-type gene [113]. certainly afford the opportunity to examine gene-gene interactions Interestingly these flies were embryonic lethal when expressed and allow the detection of effects at a distance. They raise mecha- throughout the larvae and generated a mutant eye phenotype nistic questions that may ultimately only be answered in more GMR when controlled by the GAL4 promoter. When the flies were reductionist experimental systems. Given those attributes the crossed with flies transgenic for Ab1–42 the embryonic lethal phe- investigator must decide whether the transgenic or other animal notype was abolished, indicating that the Ab interaction inhibited model approaches are suitable to address their particular biologic the protease inhibitory activity of the serpin molecule. Although problem. the in vitro experiments indicated that Ab fibril formation was inhibited by the interaction, effects on the Ab phenotype of the flies Acknowledgments were not reported. This work was supported by the National Institutes of Health 2.15. Gelsolin, transthyretin and AD research Grants AG019259 and AG030027.

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