Cognitive Impairment in Transgenic Mouse Models of Amyloid Deposition

The identification of the Aβ peptide as a major component of amyloid deposited in brain vessels and subsequently of parenchymal plaques in the brains of Alzheimer’s victims [1] led to a focus on this molecule as a key element in the pathophysiology of Alzheimer’s disease (AD). Subsequent work found that some mutations causing the disease occurred in the amyloid precursor protein (APP) that is processed, in some circumstances, into the Aβ peptide [2]. Ultimately, all mutations causing AD have been demonstrated to result in overproduction of the long variant of the Aβ peptide [3]. Thus the pathology, genetics, and the in vitro neurotoxicity of the Aβ peptide has led to a focus on the aggregation and accumulation of this material as a prime target for therapies designed to treat AD.As for other disorders, development of animal models to understand amyloid pathology became an important research goal. Our lab and many others attempted to mimic the AD condition in rodent brain by direct injections of the peptide [4, 5]. These efforts were largely unsatisfactory. Similarly, a number of other research groups attempted to create transgenic models overexpressing various forms of the APP gene. After many failures to create models that deposit amyloid in a manner similar to AD, and after a couple of retracted claims, the first APP transgenic mouse that deposited amyloid in a manner similar to AD was developed [6]. Because of the platelet-derived growth-factor promoter used, this mouse is referred to as the PDAPP mouse. Shortly thereafter, other APP transgenic mice were successfully developed with amyloid pathology similar to AD: the Tg2576 mouse of Hsiao [7] and the APP23 mouse of Novartis [8]. In a variety of informative ways, these mice have been crossed with other genetically modified mice. One of these was the presenilin-1 (PS1) mouse of Duff [9]. The presenilin gene codes for a critical component of the gamma secretase complex, which determines the length of the Aβ peptide during processing of the APP. Mutations of this gene can also cause early-onset AD in humans. Our group and several others found that crosses between the PS1 mice and the APP mice resulted in accelerated amyloid pathology as the mice age [10]. This chapter focuses on the behavioral abnormalities in the APP transgenic models. It is important to recognize that these are not models of AD, as they lack the tau pathology and the neuron loss found consistently in the human disorder. However, the mouse models mimic in considerable detail the amyloid deposition found in the human disease, and they are all largely similar, irrespective of the mutations used or the promoters employed.