Nonhuman Primate Models of Alzheimer-Like Cerebral Proteopathy

Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Current pharmaceutical design (Impact Factor: 3.45). 01/2012; 18(8):1159-69. DOI: 10.2174/138161212799315885
Source: PubMed


Nonhuman primates are useful for the study of age-associated changes in the brain and behavior in a model that is biologically proximal to humans. The Aβ and tau proteins, two key players in the pathogenesis of Alzheimer's disease (AD), are highly homologous among primates. With age, all nonhuman primates analyzed to date develop senile (Aβ) plaques and cerebral β-amyloid angiopathy. In contrast, significant tauopathy is unusual in simians, and only humans manifest the profound tauopathy, neuronal degeneration and cognitive impairment that characterize Alzheimer's disease. Primates thus are somewhat paradoxical models of AD-like pathology; on the one hand, they are excellent models of normal aging and naturally occurring Aβ lesions, and they can be useful for testing diagnostic and therapeutic agents targeting aggregated forms of Aβ. On the other hand, the resistance of monkeys and apes to tauopathy and AD-related neurodegeneration, in the presence of substantial cerebral Aβ deposition, suggests that a comparative analysis of human and nonhuman primates could yield informative clues to the uniquely human predisposition to Alzheimer's disease.

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    • "A range of animal species are used as experimental models for AD pathologies [129]. These models vary from invertebrate animals such as Drosophila [130], C elegans [131], and zebrafish [132] to rodents [133] [134] and non-human primates [135] [136], although mice are most often used to investigate AD pathogenesis . Even the most resilient transgenic mouse models for AD exhibit the rarer familial form of the disease, whereas sporadic AD is the most common [137]. "
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    ABSTRACT: Preclinical studies are essential for translation to disease treatments and effective use in clinical practice. An undue emphasis on single approaches to Alzheimer's disease (AD) appears to have retarded the pace of translation in the field, and there is much frustration in the public about the lack of an effective treatment. We critically reviewed past literature (1990-2014), analyzed numerous data, and discussed key issues at a consensus conference on Brain Ageing and Dementia to identify and overcome roadblocks in studies intended for translation. We highlight various factors that influence the translation of preclinical research and highlight specific preclinical strategies that have failed to demonstrate efficacy in clinical trials. The field has been hindered by the domination of the amyloid hypothesis in AD pathogenesis while the causative pathways in disease pathology are widely considered to be multifactorial. Understanding the causative events and mechanisms in the pathogenesis are equally important for translation. Greater efforts are necessary to fill in the gaps and overcome a variety of confounds in the generation, study design, testing, and evaluation of animal models and the application to future novel anti-dementia drug trials. A greater variety of potential disease mechanisms must be entertained to enhance progress.
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    • "Thus, modeling the full range of events of human aging-related diseases in any species, even in the most closely related to humans as other primates or in transgenic organisms expressing human disease-related genes, results extremely difficult if not impossi- ble. Despite all, several animal models have been generated and used in this context, from invertebrates such as Caenorhabditis elegans (Wolozin et al., 2011) or Drosophila melanogaster (Rincon-Limas et al., 2012; Thackray et al., 2014) to several primate species as marmosets or macaques (Heuer et al., 2012). Albeit the most widely developed and used models are indisputably transgenic mice. "
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    ABSTRACT: Prion diseases or Transmissible Spongiform Encephalopathies (TSEs) are a group of fatal neurodegenerative disorders affecting several mammalian species being Creutzfeldt-Jacob Disease (CJD) the most representative in human beings, scrapie in ovine, Bovine Spongiform Encephalopathy (BSE) in bovine and Chronic Wasting Disease (CWD) in cervids. As stated by the "protein-only hypothesis", the causal agent of TSEs is a self-propagating aberrant form of the prion protein (PrP) that through a misfolding event acquires a β-sheet rich conformation known as PrP(Sc) (from scrapie). This isoform is neurotoxic, aggregation prone and induces misfolding of native cellular PrP. Compelling evidence indicates that disease-specific protein misfolding in amyloid deposits could be shared by other disorders showing aberrant protein aggregates such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic lateral sclerosis (ALS) and systemic Amyloid A amyloidosis (AA amyloidosis). Evidences of shared mechanisms of the proteins related to each disease with prions will be reviewed through the available in vivo models. Taking prion research as reference, typical prion-like features such as seeding and propagation ability, neurotoxic species causing disease, infectivity, transmission barrier and strain evidences will be analyzed for other protein-related diseases. Thus, prion-like features of amyloid β peptide and tau present in AD, α-synuclein in PD, SOD-1, TDP-43 and others in ALS and serum α-amyloid (SAA) in systemic AA amyloidosis will be reviewed through models available for each disease. Copyright © 2015. Published by Elsevier B.V.
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    • "Another human-exclusive trait is the long period of healthy post-reproductive life of women, in stark contrast to other primates, which usually die before menopause (Walker and Herndon, 2008). Humans are also susceptible to such age-related diseases as Alzheimer's disease and Parkinson's disease, which are absent in all other primates (Finch and Austad, 2012; Heuer et al., 2012). Because this unique human aging phenotype emerged during the 6 million years since the human line diverged from that of the chimpanzee and bonobo, it must result from a relatively small number of genetic changes. "
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    ABSTRACT: We present the first longitudinal data on cognitive and motor aging in the chimpanzee (Pan troglodytes). Thirty-eight adult female chimpanzees (10-54 years old) were studied. The apes were tested longitudinally for 3 years in a modified Primate Cognition Test Battery, which comprised 12 tests of physical and social cognition. The chimpanzees were also administered a fine motor task requiring them to remove a steel nut from rods of various complexity. There was little evidence for an age-related decline in tasks of Physical Cognition: for most tasks, performance was either stable or improved with repeated testing across age groups. An exception was Spatial Memory, for which 4 individuals more than 50 years old experienced a significant performance decline across the 3 years of testing. Poorer performance with age was found in 2 tasks of Social Cognition, an attention-getting task and a gaze-following task. A slight motor impairment was also observed, with old chimpanzees improving less than younger animals with repeated testing on the simplest rod. Hormonal status effects were restricted to spatial memory, with non-cycling females outperforming cycling females independently of age. Unexpectedly, older chimpanzees were better than younger individuals in understanding causality relationships based on sound.
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