Transgenic Mouse Models of Alzheimer’s Disease: Behavioral Testing and Considerations

Excerpt

One hundred years ago, the German psychiatrist and neuropathologist Alois Alzheimer gave a lecture in which he identified a disease of the cerebral cortex [1] that would ultimately bear his name: Alzheimer’s disease (AD). In individuals with this condition, the cerebral cortex is thinner than normal and senile plaques, along with neurofibrillary tangles (NFTs), are found in the brain [2]. In the early 1980s, the biochemical characterization of senile plaques in patients with Down’s syndrome and AD led to the identification of amyloid-β (Aβ) peptide as a major component. Thereafter, it was determined that Aβ is a product of the Aβ protein precursor (APP). The importance of Aβ/APP in the pathogenesis of AD is evidenced by the fact that genetic mutations in the APP gene invariably cause AD in cases with the early onset familial form of the disease [3–5]. The relationship between APP and Aβ caused the research community to respond with quick enthusiasm for Aβ and laid the foundation for the amyloid cascade hypothesis [4,6]. The amyloid cascade hypothesis states that mutations in APP (or other genes) lead to an increase in Aβ and that this then leads to disease. While the original hypothesis [6] posited Aβ fibrils as the major mediator of the disease, a more recent incarnation of the hypothesis [4] proposes smaller oligomeric forms of Aβ as key. In both cases, Aβ is viewed as being important in mediating the neuronal and synaptic toxicity that leads to the deterioration of cognition [7]. Likewise, a steady influx of research began to elucidate the role of NFTs and their principal protein component, phosphorylated tau, in the brain and how these pathological entities related to the symptomatology of AD [8]. While the pathological significance of Aβ and NFTs in disease, as well as their interaction is still under much discussion [9,10], the majority of investigators in the field are convinced that they play fundamental roles in the onset and progression of AD. That said, other theories of AD, unrelated to NFTs and Aβ deposits, are also being actively pursued (for review see [11–15]). Nevertheless, the development of transgenic mouse models of AD over the last decade has primarily focused on the pathological markers (NFTs and senile plaques), and such transgenic models have become promising tools to decipher the mechanistic importance of tau phosphorylation and Aβ deposits, as well their relationship between each other and the other pathological changes.

While seemingly obvious, it is important to remember that the validity of a mouse model of disease is tightly linked to the ability of the animal to mimic the signs of the disease—in the case of AD, cognitive decline. The aim of this review is to discuss cognitive function in transgenic mouse models focused predominantly on Aβ and tau models and, thereafter, the validity of these models to study AD and the mechanistic questions that have arisen based on their behavioral phenotype [16,17].