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COM M E N TA RY
The benefits and limitations of animal models for translational research in neurodegenerative diseases
2010 Nature America, Inc. All rights reserved.
Mathias Jucker
Age-related neurodegenerative diseases are largely limited to humans and rarely occur spontaneously in animals. Genetically engineered mouse models recapitulate aspects of the corresponding human diseases andare instrumental in studying disease mechanisms and testing therapeutic strategies. If considered within the range of their validity, mouse models have been predictive of clinical outcome. Translational failure is less the result of the incomplete nature of the models than of inadequate preclinical studies and misinterpretation of the models. This commentary summarizes current models and highlights key questions we should be asking about animal models, as well as questions that cannot be answered with the current models.
Natural animal modelsAge-related neurodegenerative diseases are largely human-specific diseases. Although aged nonhuman primates and some other higher-order animal species show aspects similar to those of human brain aging, these animals generally do not readily develop the full neuropathological or clinical phenotypes seen in humans1,2 (with a few possible excep-
tions, such as mutant SOD-linked canine degenerative myelopathy, resembling amyotrophic lateral sclerosis (ALS))3.
Aged mammals, similar to aged, cognitively normal humans, can develop the neuropatho-logical lesions that define human Alzheimers disease. For example, cerebral -amyloidosis spontaneously occurs in aged nonhuman primates, bears and dogs47. Neurofibrillary tangles have been described in aged nonhuman primates, bears and sheep4,810. No such
spontaneously occurring lesions have been reported in aged laboratory rodents or lower-order species.
Paradoxically, the paucity of age-related neurodegenerative diseases in nonhuman species could yield some mechanistic insights into the etiology of the human diseases. At least for nonhuman primates, the amino acid sequences of the disease-defining pathogenic proteins are very similar to, or predict an even more pathogenic protein than, the human sequences1114. Differences in chaperones, proteasomal and autophagosomal clearance mechanisms, lifespan or comorbid conditions are considered causes for the apparent resistance of nonhumans to age-related neurode-generation.
Familial cases are similar to idiopathic cases
The majority of human neurodegenerative diseases are sporadic and of unknown etiology. However, aside from age of onset, idiopathic Alzheimers disease, Parkinsons disease, frontotemporal lobar degeneration (FTLD) and ALS are clinically and neuropathologically similar to their most common familial forms1518. Phenotypic similarities between...