App-Based Transgenic Models: The Tg2576 Model

The search for a good animal, preferably mouse, model of Alzheimer's disease (AD) is one of the most imperative in present medical research, given the increasing prevalence of this disorder in an aging population and its enormous social, economic, and personal impact. In 1996, Karen Hsiao and colleagues showed that transgenic mice, which overexpress a human APP cDNA transgene from a Swedish family whose members showed early onset, familial AD (Tg2576 mice) were cognitively impaired at around 10 months of age and also showed pathophysiological characteristics of AD, notably deposits of amyloid. Much work followed this original publication, yet even now there is only limited consensus as to when, and to what extent, cognition is impaired in this model. This work is reviewed here, as well as research on the neuropathophysiological mechanisms by which the mice become cognitively impaired. The fundamental validity of the Tg2576 model and the role of beta-amyloid in the disease processes seen in both Tg2576 mice and humans with AD are also considered.Most research suggests that Tg2576 mice are moderately cognitively impaired by 12 months of age, and this laboratory therefore first started work on a cohort this age. Further work was done on cohorts aged 3, 9, and 21 months. Marked cognitive deficits were found in three paradigms: reference memory in a Y-maze motivated by escape from shallow water (paddling Y-maze); social memory for a juvenile mouse; and habituation to an open field over 24 h. Only the former has so far been shown unambiguously to be age-dependent. The latter two tests are simple to perform, so hold great promise as potential screens for new therapeutic agents. Reference memory in an appetitively motivated T-maze with both response and visual cues may also reveal cognitive impairments of an acceptable magnitude. However, the development of a new Tg2576 line based on a 129 mouse substrain with good behavioral characteristics may hold the greatest promise for future test development.