Animal models of neurodegenerative diseases

Abstract

The prevalence of neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), increases with age, and the number of affected patients is expected to increase worldwide in the next decades. Accurately understanding the etiopathogenic mechanisms of these diseases is a crucial step for developing disease-modifying drugs able to preclude their emergence or at least slow their progression. Animal models contribute to increase the knowledge on the pathophysiology of neurodegenerative diseases. These models reproduce different aspects of a given disease, as well as the histopathological lesions and its main symptoms. The purpose of this review is to present the main animal models for AD, PD, and Huntington's disease.

Neurodegenerative diseases; Alzheimer's disease; Parkinson's disease; Huntington's disease; animal models

Introduction

The incidence of neurodegenerative diseases increases with age and, considering the aging process of the population worldwide, the prevalence of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) is expected to rise in the next years. This is particularly true for AD, the most common form of dementia, accounting for approximately 50-60% of all cases and representing a major public health concern with significant social and economic impact.¹

There is still no curative treatment for AD or other neurodegenerative diseases, but ongoing trials are presently evaluating new therapeutic strategies.² The identification of effective disease-modifying drugs depends on the accurate understanding of the etiopathogenic mechanisms underlying the disease so that strategies that may eventually preclude its development or at least lessen its progression may be suggested.

To increase the knowledge on the etiopathogenic mechanisms of neurodegenerative diseases, a series of animal models is currently being used. These models aim to reproduce the causes, the pathological lesions, or the symptoms of a given disease.³ Besides providing insights into the pathophysiology of the diseases, animal models are of paramount importance to assess the efficacy of potential treatments before conducting clinical trials in humans. In the present review, we present data on animal models for AD, PD, and Huntington's disease (HD).

Animal models of Alzheimer's disease

AD affects mainly people over 60 years old and its initial presentation is usually memory impairment, but later symptoms include visuospatial, language, and executive dysfunctions. At present, there is no effective disease-modifying strategy in AD, and the available drugs are indicated to improve cognitive and behavioral symptoms.⁴

Although animal models have greatly advanced the understanding of AD pathogenesis, the lack of knowledge concerning its causes makes it difficult to develop a model exhibiting all AD features, which hinders the discovery and characterization of effective drugs. Currently, the most employed animal models were developed based on known genetic mutations associated with AD.⁵ However, the vast majority of AD cases (over 90%) are sporadic, and the underlying causes are unknown. Therefore, these genetic-based AD animal models do not recapitulate all features of sporadic AD and do not cover all factors that may influence the etiopathogenesis of sporadic AD, such as apolipoprotein E. An additional complicating factor is that AD animal models do not exhibit the extensive neuronal cell loss observed in human patients.⁶

The histopathological hallmark of AD is the accumulation of neurofibrillary tangles and amyloid plaques. Extracellular amyloid plaques are formed from β-amyloid protein peptides (Aβ), which are fragments formed by cleavage of amyloid precursor protein (APP).⁷ APP can be processed by α-and γ-secretases, generating a non-amyloidogenic product, or by β- and γ-secretases, generating Aβ peptides, which are amyloidogenic and are prone to form plaques (Figure 1). However, there is no direct correlation between the number of cortical plaques and cognitive deficit in AD patients, and many individuals have amyloid plaques without cognitive impairment or dementia.⁸ Moreover, the amount and the topography of the senile plaques are not correlated with the severity of dementia, and the amyloid deposition seems to remain stable during the progression of the disease.⁹ The clinical progression of AD symptoms is not congruent with the progression of the amyloid deposition in the human brain, but it seems closely related to the progression of tau pathology.¹⁰ This set of data indicates that factors other than amyloid deposits might have a role in the disease progression.¹¹ For instance, soluble oligomeric Aβ species formed by 1 to 30 Aβ amino acids correlate better than amyloid plaques with cognitive decline in both humans and AD transgenic mice. Synaptic loss that might be caused by the neurotoxic effect of soluble Aβ oligomers and/or tau pathology is also directly related to cognitive impairment.¹¹,¹²

Figure 1
Basic pathophysiology of Alzheimer's disease. The amyloid precursor protein (APP) can be cleaved either by a “non-amyloidogenic pathway” or by the so-called “amyloidogenic pathway.” In the non-amyloidogenic pathway, the APP is first cleaved by α-secretase, releasing a large fragment of APP (sAPPα), which is later digested by γ-secretase, producing non-toxic p3. In the amyloidogenic pathway, the APP is first processed by BACE-1 (a β-secretase), producing a fragment (sAPPβ) that will be subsequently cleaved by γ-secretase. The resulting protein of this “amyloidogenic pathway” is the toxic β-amyloid. In patients with presenilin mutations, the action of γ-secretase is disturbed and the production of β-amyloid is increased. The accumulation of insoluble β-amyloid leads to the formation of senile plaques and to the activation of kinases. β-amyloid can also activate GSK3β, an enzyme that modulates the phosphorylation of the tau protein. The accumulation of hyperphosphorylated forms of tau is toxic for the cell, leading to the formation of neurofibrillary tangles, which are associated with the activation of kinases and neuronal death.

As Aβ is closely involved in AD pathogenesis, AD rodent models were generated by intracerebral infusion of Aβ peptides.¹³,¹⁴ Importantly, direct intracerebral injection of Aβ peptides causes learning and memory deficits, as well as neuropathological changes that resemble human AD, including inflammation, microglial activation, and limited cell loss. The infusion model allows researchers to administer defined amounts of a specific Aβ species of known sequence and length, rather than waiting several months (i.e., aging process) for the development of pathological changes in transgenic animals. Aβ infusion models are very useful for pre-clinical drug testing as they can deliver experimental results, including plaque pathology, within a timeframe of few weeks.¹³ However, the concentration of the Aβ administered is much higher than the Aβ levels found in the brain of AD patients, leading to brain alterations that surpass the effect of aging on AD progression.¹⁴ Conversely, genetically modified mice overexpressing APP or Aβ₄₂ accumulate Aβ plaques and soluble Aβ oligomers in an age-dependent manner.¹⁵ These APP mouse models display progressive Aβ deposition in both diffuse and neuritic plaques, cerebral amyloid angiopathy, astrocytosis, microgliosis, mild hippocampal atrophy, neurotransmission changes, and cognitive and behavioral deficits.¹⁴

Intracellular neurofibrillary tangles are formed due to hyperphosphorylation and oligomerization of tau, a microtubule-associated protein mainly present in axons.¹⁶,¹⁷ APP mouse models do not develop neurofibrillary tangles and exhibit little neuronal loss, although hyperphosphorylated tau can be observed in different brain regions.¹⁸ Mice overproducing Aβ do not exhibit neurofibrillary tangles as well. However, Aβ pathology can activate kinases, downregulate phosphatases, and impair tau degradation, leading to tau pathology.⁶ These data supports the “amyloid cascade theory,” according to which the accumulation of Aβ is the initial pathophysiological event in AD, leading to tau aggregation, synaptic loss, and cell death.⁹ It has been shown that removal of Aβ via immunotherapy also leads to the removal of hyperphosphorylated tau aggregate.¹⁹ Aβ oligomers impair proteasome activity, contributing to the age-related pathological accumulation of Aβ and tau in humans and AD mouse models.²⁰,²¹ Mice expressing both mutated APP and tau exhibit greater neurofibrillary tangle pathology as compared to mutated tau mice, further suggesting that Aβ accumulation leads to tau pathology.²² In addition, Aβ peptide injection into the brain of tau transgenic mice exacerbates tau pathology.²²,²³ Crossing APP transgenic mice with tau knockout mice prevents all cognitive deficits associated with the presence of APP, indicating that tau pathology activation via Aβ is necessary for cognitive impairment.²⁴ Conversely, Aβ accumulation is not altered by the absence of tau. As mentioned before, APP transgenic mice do not develop extensive neurofibrillary tangles, and tau remains soluble.¹⁸ Indeed soluble tau might be more important to the disease than aggregated tau.

During AD progression, the axonal protein tau accumulates within dendritic spines, impairing synaptic function.²⁵ Using tau knockout mice and truncated tau expressing mice, it has been shown that the tau protein present in the dendrites can target the protein kinase Fyn to the postsynaptic terminals, where it phosphorylates the NR2B subunit of the N-methyl-d-aspartate (NMDA) receptor. This receptor increases NMDA localization in postsynaptic membrane and, hence, the influx of calcium into the neuron, facilitating excitotoxicity.²⁶ Using an APP mouse model of AD, it has been demonstrated that Aβ oligomers can also regulate NMDA receptor cellular trafficking.²⁷ Therefore, tau knockout mice and APP overexpressing mice have been useful for elucidating essential mechanisms related to AD pathophysiology.

Knockout mice for genes involved in APP processing and secretion have also been generated. Presenilin is an important component of the γ-secretase complex and the knockout of presenilin 1 is lethal due to developmental defects in both the central nervous and skeletal systems.²⁸ These data indicate that presenilin 1 may be involved in physiological functions other than Aβ production and that presenilin 1 blockage might not be a good pharmacological strategy to treat AD. Presenilin 2 knockout mice exhibit no change in APP processing, although lack of presenilin 2 can exacerbate the lethal phenotype of presenilin 1.²⁹ The knockout of BACE1, which is the β-secretase enzyme, does not lead to any obvious alteration other than the absence of Aβ production.³⁰ Thus, BACE1 appears to be a potential target for AD treatment. Supporting this hypothesis, crossing the APP transgenic mice, Tg2576 mice, with the BACE1 knockout mice, resulted in a mouse that did not exhibit cognitive decline, cholinergic dysfunction, and high levels of Aβ, which were observed in the Tg2576 mice.³¹

Although AD mouse models have greatly contributed to elucidate different aspects of disease pathogenesis, so far no drug has been developed to treat AD using such models. The extensive neuronal cell loss that takes place in AD patients is not observed in AD models. Moreover, tau pathology is absent in most APP models. An animal model exhibiting most of the typical pathological aspects of AD, including increased neuronal death, seem to be necessary to select drugs that could have a greater potential in AD. Transgenic mice expressing mutated presenilin 1 and 2 do not exhibit any major phenotype.³²-³⁴ However, when these presenilin mice were crossed with APP overexpressing mice, the resulting double mutant mice displayed increased Aβ42/Aβ40 ratio, accelerated Aβ pathology, neuronal loss, and cognitive decline.³⁵ However, neurofibrillary tangles were very rare in this double transgenic model. To overcome this problem, a triple transgenic mouse expressing mutated tau was developed, and this AD mouse model exhibit most of the AD-related features, including tau pathology.³⁶ To generate this triple mutant, transgenic constructs (mutant APP and tau) were microinjected into single-cell embryos from homozygous mutant presenilin 1 mice, thereby preventing segregation of APP and tau genes in subsequent generations. In accordance with the amyloid cascade theory, these triple transgenic mice develop Aβ plaques prior to neurofibrillary tangles, with a temporal and spatial profile equivalent to AD, in addition to inflammation, synaptic dysfunction, and cognitive decline.³⁶ Due to the growing number of AD rodent models, this review only mentioned a few representative mouse models of AD. For an updated overview of available genetically modified AD models, we refer the readers to specialized websites, such as http://www.alzforum.org.

Besides mammal models, zebra fish have been increasingly recognized as a model organism for studying AD. Zebra fish present some characteristics that make them an interesting model for central nervous system (CNS) diseases, such as short time to reach sexual maturity and a high reproductive rate.³⁷ Moreover, their embryos have external development and are transparent, thus allowing direct observation of embryogenesis and CNS formation. Zebra fish may present complex behaviors in memory and conditioned responses tasks. Transgenic zebra fish models may be of particular interest for investigating the neurodegeneration associated with taupathy.³⁷

In addition to vertebrate models of AD, invertebrate animals, such as Caenorhabditis elegans and Drosophila, may be suitable to study AD, as they have short reproduction time, short life span, known genomics, a variety of phenotypes, and are able to express human genes of interest. These invertebrate animals allow rapid construction of different transgenic models, boosting genetic and drug screens to identify mechanisms related to age-dependent neurodegeneration.

Drosophila expressing genetically modified tau exhibits adult onset, progressive neurodegeneration, early death, enhanced toxicity of mutant tau, and accumulation of abnormal tau, but no neurofibrillary tangles.³⁸ Intracellular inclusion resembling neurofibrillary tangles can be provoked in wild-type tau expressing flies when glycogen synthase kinase 3β (GSK-3β) activity is increased, as GSK-3β can promote hyperphosphorylation of tau and subsequent aggregation.³⁹ A number of APP Drosophila models has also been developed, and it has been demonstrated that Drosophila can produce Aβ peptide and develop neurodegeneration and memory decline.⁴⁰,⁴¹ Moreover, Drosophila overexpressing APP and BACE have been used for drug testing. Administration of either BACE inhibitor or γ-secretase inhibitor increased survival rates of this Drosophila model.⁴²

C. elegans have only about 302 neurons, greatly facilitating the study of neuronal morphology and physiology. Moreover, about 65% of the human disease genes have a counterpart in the nematode's genes.⁴³ Although C. elegans are not able to process APP to form Aβ peptide, C. elegans expressing Aβ₄₂ peptide intracellularly in muscle cells exhibit aggregation and, hence, muscle dysfunction (paralysis phenotype).⁴⁴ This model provides important insights into Aβ toxicity, but does not allow screening of genetic or chemical modifiers of APP processing. Transgenic nematodes expressing Aβ₄₂ in neurons develop amyloid deposits, but display only a very mild phenotype.⁴⁵ To create nematode tau pathology models, either wild-type or mutated human tau proteins were expressed in C. elegans neurons, inducing age-dependent motor neuron dysfunction, neurodegeneration, and locomotor deficits due to impaired neurotransmission.⁴⁶,⁴⁷ In conclusion, although invertebrates lack the neuronal cognitive complexity of mammals, they represent a feasible model to study AD mechanisms and to perform drug screening.

Even though these animal models provided valuable and important data concerning the pathophysiology of AD, the recent failure of anti-amyloid immunotherapy in AD points the limits of the pathophysiological paradigms established from these animal models. Indeed, new animal models for sporadic AD taking into account the genetic variability and the immunological factors that may influence the pathophysiology of the disease are required for the development of effective disease-modifying drugs for AD.

Animal models of Parkinson's disease

PD is the second most common age-related human neurodegenerative disorder. Prevalence rate varies from 1 to 4% in people over 60 years old.⁴⁸,⁴⁹ However, prevalence rates up to 10% have been reported in elderly people depending on the epidemiological approach, diagnostic criteria, and population survival rate.

The main histopathological hallmark of PD is the loss of dopaminergic neurons in the substantia nigra pars compacta. The progressive striatal dorsoventral dopamine depletion leads to the cardinal motor signs of PD, bradykinesia, resting tremor, rigidity, and postural instability.⁵⁰ Therapeutic strategy is based on dopamine analogs, dopamine-degrading enzyme inhibitors, and deep brain stimulation, but none is able to halt the progressive neuronal death.⁵¹

Olfactory deficits are frequently evident in the very early stage of PD. Sleep abnormalities and autonomic failure accompanies motor symptoms. Dementia is often observed in the later stages of PD. In consonance with this broad spectrum of non-motor symptoms, histopathological abnormalities have been also described in other encephalic areas, comprising the dorsal motor nucleus of the vagus, nucleus basalis of Meynert, locus coeruleus, raphe nuclei, amygdala, olfactory bulb, neocortex, and hypothalamus.⁵² Interestingly, many clinical studies have shown that non-motor symptoms may antedate the onset of typical motor signs in PD, stressing the need for understanding the molecular pathways that might trigger the neurodegenerative process.⁵³

The cellular pathological hallmark for PD is the presence of small eosinophilic inclusions known as Lewy bodies in all the affected brain areas. Lewy bodies are composed of unbranched α-synuclein filaments and ubiquitin, and most likely result from ineffective protein degradation. Post-mortem analysis of brain from PD patients has shown that α-synuclein inclusions emerge in a predictable order in different parts of the brain and may be linked to the progressive stages of this disease.⁵²

Although the etiopathogenesis of PD is not yet clarified, animal models have provided a better understanding of the cellular and molecular mechanisms underlying the progressive neurodegenerative process. In the fifties, pharmacological models based on the administration of monoamine-depleting drugs had an important role in demonstrating the relationship between dopamine depletion and Parkinson-like motor symptoms as well as the efficacy of L-dopa therapy. Nevertheless, reserpine and haloperidol models had serious limitations in mimicking PD pathogenesis since drug-treated animals exhibited transient striatal dopamine depletion not associated with the typical neurodegeneration in substantia nigra.⁵⁴ However, the pivotal role played by these models in assessing the therapeutic efficacy of drugs still in current clinical use cannot be undermined.

The so-called neurotoxin-based models of PD are the most effective in reproducing irreversible dopaminergic neuron death and striatal dopamine deficit in nonhuman primates and rodents. MPTP (1-methyl-4-phenyl-1,2,3,6-terahydropyridine), 6-OHDA (6-hydroxy-dopamine), and rotenone are so far the most widely used compounds. They are particularly attractive for inducing cytotoxicity by oxidative stress mechanisms, as brain from PD patients show decreased levels of reduced glutathione and oxidative modifications to DNA, lipids, and proteins.⁵⁵,⁵⁶

Interestingly, MPTP was accidently discovered during the investigations of the potential factors that led young addicts to develop PD-like symptoms. MPTP was found to be the heroin contaminant responsible for parkinsonism in these subjects.⁵⁷ MPTP can be administered systemically since it is highly lipophilic and freely crosses the blood brain barrier. Astrocytes and endothelia convert MPTP into the active neurotoxic MPP+ (1-methyl-4-phenylpyridinium), which is taken up by dopaminergic neurons through the dopamine transporter. MPP+ interacts with the mitochondrial complexes I-III-IV, inhibiting the electron transport chain and inducing ATP depletion and oxidative stress.⁵⁸ MPP+ is also linked to impairment of glutamate uptake by astrocytes and neuronal apoptosis.⁵⁹,⁶⁰

MPTP administration to nonhuman primates is the experimental model that more closely resembles the pathological features of PD, including nigrostriatal dopamine depletion and extrastriatal dopamine, noradrenaline, and serotonin changes observed in PD patients.⁶¹ In this model, the motor symptoms are closely similar to those observed in man (akinesia, bradykinesia, rigidity, and postural abnormalities) except for rest tremor. The symptoms are also reversible by all dopaminergic drugs known to be effective in PD. This model has been extensively used to investigate new pharmacological treatments for PD, as well as strategies to avoid treatment-related dyskinesia.⁶² No typical Lewy bodies are observed in a MPTP primate model, but α-synuclein immunoreactivity is enhanced in the nigrostriatal system and in many brain areas.⁶³ The relevant role for neuroinflammation in PD pathology, specifically IFN-γ and TNF-α inducing early microglial activation that precedes neuronal death, has been recently highlighted in this model.⁶⁴ In mice, MPTP also induces nigrostriatal dopaminergic degeneration, making it a widely used model. More recently, Prediger et al. showed that intranasal infusion of MPTP in rodents causes motor impairments and olfactory and cognitive deficits that resemble the different stages of PD.⁶⁵,⁶⁶

Rotenone, a pesticide used in farming, is also highly lipophilic and easily crosses the blood brain barrier. Rotenone is a high-affinity inhibitor of mitochondrial complex I, but unlike MPTP, its entrance into cells is not dependent on a specific transporter. Rotenone cytotoxicity is based on oxidative stress and reactive oxygen species production.⁶⁷ High doses of rotenone can induce generalized neurodegeneration, so studies have been directed to chronic low-dose regimen in systemic administration of this compound in rodents. In this condition, α-synuclein positive Lewy bodies are observed in the nigrostriatal system.⁵⁴

Unlike MPTP and rotenone, 6-OHDA does not cross the blood-brain barrier and it must be injected into the brain through a stereotaxic-guided surgical procedure. 6-OHDA is taken up into the dopaminergic neurons due to its high affinity to dopamine transporter. Once inside neurons, 6-OHDA is readily oxidized in reactive oxygen species leading to electron transport chain inhibition and oxidative stress.⁶⁸ 6-OHDA is usually injected unilaterally in the substantia nigra or in the striatum (retrograde degeneration). The unilateral injection allows the evaluation of neuron cell death and molecular parameters in the lesion hemisphere compared with the intact contralateral one. Dopamine depletion, percentage of neuronal cell death necessary to cause motor symptoms, and behavioral deficits have been assessed in this model. Neither Lewy bodies nor olfactory deficits were observed in 6-OHDA-treated animals.⁶⁹ This model has been proven to be useful to study glia involvement in the neurodegenerative process. For instance, Saura et al. showed that glia activation by interleukin-1β before 6-OHDA injection protects rather than stimulates neuron cell degeneration.⁷⁰ Conversely, microglia activated by overexpression or aberrant expression of α-synuclein secretes inflammatory cytokines and reactivates oxygen species that contribute to neurodegeneration.⁷¹

Although most PD cases are sporadic, approximately 5 to 10% are inherited. At least 16 gene loci (PARK1-16) have been implicated in PD, but the heritability is not fully understood. The most common cause of familial PD is the dominant mutation in leucine-rich repeat kinase 2 (LRRK2), an enzyme involved in the cytoskeleton dynamics and synaptic vesicle function.⁷² Dominant mutation has also been linked to many important molecular pathways such as α-synuclein folding and ubiquitin-dependent proteolysis. Recessive mutation has also been involved in important mitochondrial pathways related to oxidative stress response. Although genetically modified rodents have been used for elucidating molecular pathways involved in neuron death and for developing new therapeutic strategies, none of them displays the significant neurodegeneration typical of PD.⁷³

Neuroinflammation is also considered to play an important role in PD pathogenesis since enhanced levels of cytokines are detected in post-mortem analysis of the nigrostriatal system, in the cerebrospinal fluid and in plasma from PD patients.⁷⁴,⁷⁵ LPS infusion into the substantia nigra induces microglia activation that precedes the degeneration of dopaminergic neurons. Although it has been shown that activated microglia releases TNF-α, IL-1β, nitric oxide, and reactivates oxygen species after LPS injection, a direct cause-effect association between these mediators and neuronal cell death has not been established yet in this model.⁷⁶

It is worth mentioning the contribution of invertebrate models, particularly the Drosophila model, to assess the genetic pathways related to PD-genes. This fly model has pointed out the importance of parkin and PINK1 for mitochondrial integrity, fission-fusion events, and turn-over through autophagy, most likely acting in a common genetic pathway.⁷⁷,⁷⁸ The α-synuclein gene is the only known gene related to familial PD that does not have a homolog in Drosophila.⁷⁹ LRRK2 mutation also induces mitochondrial and dopaminergic dysfunction in Drosophila.⁸⁰ In this particular model, activation of adenosine monophosphate-activated protein kinase (AMPK), a cellular energy sensor, exerts potent protection against dopaminergic and mitochondrial dysfunction in both LRRK2 and parkin mutant flies.

Animal models of Huntington's disease

HD is an autosomal dominant inherited neurodegenerative disorder characterized by progressive motor, cognitive, and psychiatric symptoms, leading inevitably to death.⁸¹,⁸² Choreoatetosis, dementia, and an autosomal dominant inheritance is classically regarded as ‘the Huntington's triad.' A polyglutamine expansion in the amino-terminal region of the huntingtin (HTT) protein is the cause of HD, and the length of the polyglutamine repeat is inversely correlated with the age of disease onset and directly correlated with the severity of symptoms.⁸³ Although it is well established that the mutated HTT is responsible for triggering HD, the mechanisms underlying mutant HTT pathogenicity are still largely unknown. There is no data explaining why the mutant protein, which is expressed throughout the body results in the selective death of striatal medium sized spiny neurons. Cleavage of polyglutamine expanded HTT leads to the release of amino-terminal fragments containing the polyglutamine repeats, which can aggregate in neurites, cytoplasm, and nuclei. However, it is still controversial whether mutated HTT aggregates are cytotoxic or may reflect successful sequestration of toxic soluble HTT oligomers.⁸⁴,⁸⁵ Importantly, loss of striatal and cortical neurons strongly correlate with HD symptom severity.⁸⁶

Unlike the majority of AD and PD cases, which are sporadic, HD is an inherited neurologic disease caused by a single gene mutation, which made it feasible to develop animal models using genetic manipulations that closely recapitulate HD pathology. These models include transgenic mice, such as R6/2 and N171-82Q, expressing the amino-terminal region of human mutant HTT⁸⁷-⁸⁹; transgenic mice, such as yeast artificial chromosome mice (YAC128) and bacterial artificial chromosome mice (BACHD), expressing full-length human mutant HTT⁹⁰,⁹¹; and knock-in mice, such as Hdh^Q97/Q97, Hdh^Q111/Q111 and Hdh^Q150/Q150, generated by replacing the first exon of the murine HTT gene by the first exon of the human HTT gene containing expanded CAG repeats.⁹²-⁹⁴

R6/2 mice display a robust phenotype, including motor deficits, such as lack of motor coordination, abnormal gait and hypoactivity, and learning impairment, with age of onset of about four weeks.⁸⁹,⁹⁵,⁹⁶ Aggregate formation is very pronounced in R6/2 mice, with intranuclear inclusions similar to those observed in biopsy material from HD patients and occurring prior to the development of symptoms.⁸⁷,⁹⁷ These transgenic mice exhibit severe neurological symptoms and early death at 3-6 months of age.⁸⁹ The rapid onset and pronounced phenotype has made this a useful model for drug testing.⁹⁸,⁹⁹ However, despite of having a robust phenotype, R6/2 mice do not represent an accurate model of HD, as this model only expresses the amino-terminal region of the HTT protein, which is mainly composed of polyglutamines. Thus, R6/2 may be considered a model of polyglutamine diseases, such as autosomal-dominant spinocerebellar ataxias (e.g., SCA3 or Machado-Joseph disease) and X-linked spinobulbar muscular atrophy (Kennedy disease), rather than a specific HD mouse model. In that sense, the R6/2 mice can be useful to model common features of polyglutamine diseases including abnormal protein conformation promoted by polyglutamine expansion, which appears to be central to the pathogenesis. Although the clinical features and pattern of neuronal degeneration differ, all polyglutamine expansion diseases are ultimately fatal disorders that typically begin in adulthood and progress over 10 to 30 years.

YAC128 and BACHD transgenic mice, which exhibit 128 and 97 polyglutamine, respectively, in the amino-terminal region of the full-length mutant human HTT, present milder deficits than R6/2.¹⁰⁰ It has been shown that BACHD displays a stronger phenotype than that of YAC128 when both mice were tested under the same behavioral protocol.¹⁰¹ Moreover, the same study also demonstrates that Hdh^Q111/Q111 displays a very mild phenotype, exhibiting less behavioral abnormalities than R6/2, BACHD, and YAC128 mice.¹⁰¹ The knock-in mouse model of HD displays milder phenotype than R6/2 even when expressing 150 polyglutamines, as in the case of Hdh^Q150/Q150. Hdh^Q150/Q150 exhibits late-onset behavioral changes, including motor task deficit and gait abnormalities.⁹³,¹⁰² Thus, as observed in HD patients, HD mouse models with more repeats (Hdh^Q111/Q111 versus Hdh^Q150/Q150) show stronger phenotype. That is also the case for transgenic mice, as YAC46 and YAC72 mice show no clear behavioral abnormalities, while YAC128 mice display marked phenotype.¹⁰³

In general, HD mouse models displaying more severe phenotypes show earlier accumulation of HTT aggregates and premature neuronal death.¹⁰⁴ YAC128, BACHD, and Knock-in HD mice with expanded polyglutamine repeats from 97 to 150 polyglutamines display obvious HTT aggregates only at older ages and have a lifespan similar to wild-type mice.⁹⁰,⁹¹,⁹³ BACHD mice exhibit pronounced striatal and cortical atrophy, and neurodegeneration at the age of 12 months.⁹¹ However, very few HTT aggregates could be observed in BACHD brain. YAC128 mice exhibit striatal atrophy at the age of 12 months, as well as cortical atrophy at the age of 18 months.⁹⁰ Moreover, intranuclear inclusions and HTT aggregates could be observed in 12- and 18-month-old YAC128 mice, respectively. Hdh^Q150/Q150 and Hdh^Q111/Q111 mice exhibit neuronal intranuclear inclusions predominantly in the striatum, but only at older ages, such as from 15 to 22 months.⁹³,¹⁰²,¹⁰⁴ Thus, although knock-in HD mouse models accurately replicate the underlying genetic defect of HD, they do not display the robust motor deficit and neuronal cell loss observed in HD patients. In that sense, BACHD and YAC128 could be regarded as better models for drug testing.

Even though HD rodent models replicate the genetic event causing HD, most of the mouse models do not exhibit the robust neuronal cell loss that takes place in HD patients. This is the main drawback feature of not only HD mouse models, but also of AD and PD models. Future manipulations or implementations of other disease model organisms will be necessary to overcome this problem, as neurodegeneration is the major pathological event in HD, AD, and PD patients.¹⁰⁵,¹⁰⁶ Mutant HTT appears to be more toxic to larger animals, such as pigs and monkeys, than to mouse HD models.¹⁰⁷ However, despite this advantage, the high cost and more elaborated infrastructure necessary to keep these bigger animals that have a much longer life-span pose difficulties in using these types of HD models.

Small animals, including Drosophila and C. elegans, are also used as HD animal models. As stated before, the short life-span and reproduction time make these animals ideal for modeling neurodegenerative diseases and performing a number of assays, including genetic and drug screens. The identification of a Drosophila orthologue of human HTT suggests that many of the pathways in which HTT normally functions might be present in fruit flies, further supporting Drosophila as a good model to study HD.¹⁰⁸ Moreover, another interesting feature of Drosophila as an HD model is that neurodegeneration can be easily scored in the eye. Overexpressing mutant HTT in Drosophila leads to aggregate formation, neuronal death, and reduced longevity.¹⁰⁹,¹¹⁰ In addition, Drosophila HD models recapitulate many features of HD in patients, including motor deficit and learning and memory deterioration.¹¹¹,¹¹² All these features make Drosophila a suitable model for drug testing.

C. elegans expressing polyglutamine-expanded green fluorescent protein (GFP) in muscle cells were developed, and this mutant nematode exhibited aggregate formation, cellular toxicity, and paralysis in an age- and repeat length-dependent manner.¹¹³,¹¹⁴ C. elegans expressing an amino-terminal fragment of human HTT containing expanded polyglutamine in sensory and touch mechanosensory neurons have also been developed.¹¹⁵,¹¹⁶ Degeneration displayed by these C. elegans HD models are dependent on both age and polyglutamine tract length.¹¹⁵ These C. elegans models have been used to investigate proteins involved in aging and aggregation, as well as drug testing.¹¹⁷-¹²⁰ However, neuronal cell death is not robust in these HD C. elegans models.¹¹⁵,¹¹⁶

Concluding remarks

Animal models have provided significant contribution to the understanding of the pathophysiology of neurodegenerative diseases. Conversely, as neurodegenerative human diseases are heterogeneous in both pathological and clinical (or behavioral) domains, animal models only recapitulate part of this complex scenario. Moreover, much attention has been paid to genetic or transgenic animal models, while most human cases of AD and PD are sporadic, rather than familial. Together these aspects may explain the limited contribution of animal models to the development of effective disease-modifying therapeutic strategies. Therefore, there is a great challenge ahead to develop the next generation of animal models to effectively help treat and prevent neurodegenerative diseases.

This work was supported by Fundação de Amparo è Pesquisa do Estado de Minas Gerais (FAPEMIG) (grant no. APQ-00487-11), received by Fabíola Mara Ribeiro; Programa de Apoio aos Núcleos de Excelência (PRONEX) - FAPEMIG (grant no. CEX-APQ-04219-10) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (grant no. 309811/2010-4), received by Elizabeth Ribeiro da Silva Camargos; FAPEMIG (grants no. APQ-04625-10 and PPM-00567-11) and CNPq (grants no. 402853/2012-1 and 474748/2012-0) received by Antonio Lucio Teixeira.

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  2013