Animal models of human disease are seldom comprehensive. Rarely does a single system recapitulate all aspects of the human pathological process. Defining the key characteristics of a disease to be reproduced requires some knowledge of the driving force for the pathology and the symptoms. Secondary co-morbid characteristics that may be observed in the disease, but that are not critical for disease progression, would clearly be poor choices for modeling. It is not always easy to tell the difference. Before the development of molecular targets and mechanism-based approaches, pharmaceutical research and drug discovery were heavily based on animal models that reproduced symptoms seen in humans. Animals with high blood pressure or hyperglycemia were treated to determine which compounds best normalized the condition. The success of such models in predicting efficacious agents in humans depended greatly on whether the mechanisms were similar.
This approach had been relatively successful for another chronic neurodegenerative disease, Parkinson's disease. Remarkable improvement was achieved with dopaminergic neurotransmitter replacement therapy (L-dopa). The first AD models and therapeutics were based on a similar principle of symptomatic relief, alleviating the functional deficits of cholinergic systems early in the disease. Cholinergic therapies for AD were significantly less effective than was L-dopa for Parkinson's disease, and clinical evidence indicates that supplementation of cholinergic function can slow, but fails to halt, the progression of AD. The lack of effect of L-dopa on disease progression also was recognized for Parkinson's disease, suggesting that the prime mover in both diseases remained to be addressed.
Symptom-based models gave way to pathology-based models as molecular knowledge of AD expanded, and the interplay of genetic factors and the metabolism of the precursor protein to the A^ peptide found in the amyloid plaques were understood. The models based on this insight produced A^ plaques or tau filaments in the brains of transgenic mice overexpressing ^APP or tau, respectively, but failed to develop robust neuronal cell death or atrophy that resemble these events in AD. Neurophysiological and behavioral deficits were observed in young ^APP-overexpressing animals; however, they were not linked to histologically demonstrable deposits of A^, which usually developed later.
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