DEMENTIA

Mice Models of Dementia

Mice Models of Dementia

Mouse Models

Ideally, an animal model of a human neuropathological condition should exhibit ali of the behavioral and neurologicai dysfunctions known to be associated with the clinical disorder. In addition, the model should incorporate pathologic processes similar to the target condition, and it should exhibit a similar response to therapeutic intervention. However, as a reading of the papers in this series will indicate, not all of these conditions need to be satisfied for an animal model to be useful. In fact, the degree to which the specific criteria of a model are satisfied usually depends upon the specific purpose for which the model was applied. With respect to research in Alzheimer's disease, one important goal has been to develop intervention strategies for immediate reversal of symptoms. A reasonable approach to accomplishing that goal would be to test potential inte~entions in animal models with experimental lesions engineered to mimic the fund~ental neurological determinants of Alzheimer's dementia according to current understanding. In this case, the resemblance between the clinical condition and the model exists at the level of behavior and neuropathology but not necessarily at the level of etiology. For a successful treatment to be identified, only the neuropathological lesion needs to be “correct,” whereas the mechanism which produced the lesion does not necessarily need to be the same as the clinical condition.

Transgenic mouse models harboring mutations found in familial AD constitute the most widely used in vivo approach to study this disease. Few years elapsed between the description of a dominant missense APP mutation in familial AD and the generation of the first transgenic mouse bearing a mutated human APP that effectively mimicked several AD features, with prior attempts with wild-type APP made earlier. This testifies to the fast pace of this dynamic field. Indeed, the number of transgenic models of AD bearing human mutations is now so large and the literature produced so vast that only the major findings can be summarized. A detailed account of the different mouse models and their phenotypes may be found in various excellent reviews. Although invertebrate models have also been developed, because they do not constitute the mainstream of research in AD models, they will not be further considered.

Probably the main observation arising from mouse models was that excess Aß elicits cognitive impairment even in the absence of neurofibrillary tangles or neuronal loss. This finding posed this pathological change as the main culprit and therefore substantiated the amyloid cascade hypothesis of AD that favors brain amyloidosis as the cause of the disease. Consequently, the pathogenic contribution of neurofibrillary tangles was neglected. Later observations combining various transgenic models concluded that the extent of Aß plaque load does not correlate with cognitive loss. This triggered a subsequent refinement of the amyloid hypothesis that stipulated that soluble amyloid oligomers rather than insoluble deposits are responsible for synapse loss underlying the pathology (Gong et al., 2003: 10417). Presenilins are key components of the secretase complex that cleaves APP and other transmembrane ...