Purposes Of Models

Since only humans develop AD, there are no "natural" models that display all of the pathological, physiological, and symptomatic features of the human disease. The same is true for genetically engineered models, as each model has both advantages and weaknesses in recapitulating the AD phenotype. It is thus important when choosing a model for study to consider how well it is suited to answering the specific questions being asked about AD.

Development of therapeutics Testing of potential therapeutics was the motivation for developing a number of the early models of AD. A symptomatic approach was adopted similar to the one that produced effective therapy for Parkinson's disease, where the targeted deficit was in the nigrostria-tal dopaminergic system and the control of movement was monitored. Cognitive deficits in AD were modeled by subjecting hippocampally deficient mice or aged monkeys to memory tests of different sorts. Reversal of pharmacologically or lesion-induced cholinergic dysfunction in behavioral tasks by test agents was another approach.

Cholinergic therapeutics—specifically inhibitors of acetylcholinesterase—have proven to provide some benefit to patients for a limited period of time. However, this first generation of cholinergic therapeutics failed to cure or halt AD, prompting the development of models based on other pathogenic mechanisms, such as the "Aft-cascade" (Hardy and Selkoe, 2002). Such models could be used for monitoring the effects of therapeutics targeting such elements of the pathogenic cascade as plaque deposition, Aft peptide levels, glial responses, and secondary pathology. These animal models lack the profound neurodegeneration of AD, and thus they are incomplete models of AD. Combining dominant transgenes for ftAPP, PS1, and even tau had surprisingly little effect on neurodegeneration, the substrate for dementia. Nevertheless, these models, when judiciously chosen, are useful for developing possible therapeutic agents targeting key components of the pathogenic process, but the efficacy of such disease-modifying treatments in humans remains to be validated.

Probing mechanisms of AD neurodegeneration The cell-selective neurodegeneration in AD and other chronic neurodegenerative diseases and the failure to produce models with comparable neuronal cell death are unexplained. The partial models of AD pathology have been useful for teasing out mechanistic details that may apply to AD. The human disease, or cohort of diseases as some believe, is a morass of overlapping pathologies where it is difficult to determine which one(s) drive(s) the disease process, and when, during the estimated forty years of (mostly silent) progression the key players act. Modeling individual components of the multifactorial process, assessing their impact, and then combining them in different ways provide information on how they might interact in a disease state. Incorporation into a single model with the correct temporal and spatial sequencing of events would be the Holy Grail of AD.

Optimizing clinical trials A model that rapidly predicts the efficacy of an agent in producing the desired therapeutic effect, even if it is unknown whether that intervention will ultimately influence the disease, would invigorate clinical trials. The double unknown of pharmacologic efficacy and impact on the disease is discouraging. Another area in which models can contribute is in identifying potential side-effects or toxicities and to establish safe dosage ranges. Gamma secretase inhibitors have the potential to interfere with important signaling molecules, such as Notch in hematopoiesis, and this is assessed in the models.

The current models do not anticipate all possible side-effects. An Aft immunization trial designed to lower Aft levels (AN-1792, Elan) was halted by unexpected immune encephalopathy in 6% of the immunized patients. In addition, the patients who mounted an antibody response to Aft-immunization, despite weak evidence for clinical improvement, paradoxically showed an augmented shrinkage of the brain substance. A search for models capable of detecting these serious side effects is underway.

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