Mouse Models For Ad

Progress in understanding AD and developing new therapies for AD hinges upon the availability of suitable model systems for investigating the disease in the laboratory. In this vein, the application of transgenic animal technology to the pursuit of investigating AD appears to be a critically important endeavor. There are several considerations that factor into the critical role of genetic engineering in developing suitable laboratory models for AD. First, AD is an exclusively human disorder—no naturally occurring animal homologues that we can study in the lab appear to exist. AD is not transmissible, at least as far as we know, so one cannot attempt to mutate already occurring pathogens in order to generate new models. No environmental factor has yet been identified that is capable of producing AD or even aspects of the disease. Chemical or anatomical lesions to the CNS are unable to mimic the condition adequately. The only identified basis for AD is genetic. Thus, genetic engineering is the only practical route available for modeling AD in vivo.

Mouse models for AD fortunately are becoming increasingly available (see Table 2). These mouse models capitalize on the important studies, described earlier, that have identified human AD-causing mutations. Current mouse models are trans-genic mouse models expressing mutated forms of human genes (reviewed in references 27, 70, and 71). The engineered animals generally use neuron-selective promoters to drive expression of the transgenes in the CNS. Currently available lines that model AD are all derived from transgenic animals expressing mutated human APP either alone or in combination with mutated human PS-1. Transgenic lines expressing ApoE alleles are still at a relatively early stage of development.

One prominent transgenic mouse model for AD expresses a human splice-variant of APP containing the "Swedish" double mutation. This specific mutation and splice variant was identified in a large family with FAD (45, 53). This model is variously referred to as the "Swedish" mouse (after the mutation), the "Mayo" mouse (after the patent holders), the "Hsiao" mouse (after Karen Hsiao Ashe, who made the mouse), or the "Tg2576" mouse (after the mouse line number). I will refer to it as the Tg2576 mouse. Since Karen Hsiao got married and changed her last name to Ashe, my preferred eponym is out of date.

The other major mouse line that has been extensively characterized so far is the

"PDAPP" line. The name derives from the fact that it is a line expressing the human APP transgene (mutated at position 717) driven by a PDGF promoter. Other lines under development and characterization include another 717 APP mutant line, a mixture variation combining both the Swedish and 717 mutations, APP mutants combined with PS-1 mutants, and APP mutants combined with tau mutants. These mutant lines along with a few other related knockout mouse lines, and selected references, are given in Table 2.

For illustrative purposes, I will discuss some of the attributes of the Tg2576 line. I choose to focus on the Tg2576 line for two reasons. First, it is one of the lines that we have worked with in my lab, so I am most familiar with it. Second, its properties seem to be fairly representative of the various mouse lines under investigation at present. In particular, the Tg2576 line and the other major line, the PDAPP line, appear to have similar molecular and behavioral characteristics.

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