A cross-sectional and longitudinal assessment of learning, memory and neurodegenration in the 5XFAD mouse model of Alzheimer's disease

Alzheimer's disease (AD) is an age-related neurodegenerative disorder which is characterized by memory impairments, and the formation of ß-Amyloid plaques and neurofibrillary tangles within the brain (Yu and Ping, 2000, Pharmacol. Res., 42,107-114). Mutations in the amyloid precursor protein (APP) and presenilin-1 (PS1) genes have been linked to the development of early onset (familial) AD. Transgenic mice that harbour and express human APP and PS1 mutant genes, have been proposed as animal models of AD (Morrissette et al., J Biol Chem, 284,6033-7). The 5XFAD double-transgenic mouse is a novel animal model of AD which has the human APP gene with three mutations, and the PS1 gene with two mutations (Oakley et al., 2006, J. Neurosci., 26, 10129-10140). For the 5XFAD mouse to be valid animal model of AD, however, it should show similar neuropathology and memory impairment as found in humans with the disease (construct validity) (Eriksen and Janus, 2007, Behav. Genet., 37, 79-101). Also drugs used to treat AD in humans should reduce cognitive impairment in the 5XFAD mouse (predictive validity). The proposed research will validate the 5XFAD mouse as an animal model for AD by comparing age-related changes in behavior and the neuropathology in the 5XFAD mouse in a longitudinal study at 3, 6, 9, 12 and 15 months of age. Once we know to the onset and rate of cognitive decline we will assess how well drugs with known therapeutic benefits, and novel drugs with unknown effects ameliorate these deficits. Relevance and Significance: The results of this research will validate the 5XFAD mouse as an animal model for AD, and will provide other scientists in the field of AD with a detailed picture of both the behaviour and neuropathology of the 5XFAD mouse as they age. The age at which cognitive impairment first occurs, the rate of cognitive decline, will be used in future drug studies to determine the efficacy of drugs used with AD patients (Memantine and Galantamine) and novel drugs in reducing cognitive impairment in 5XFAD mice. If the results of drug studies with the 5XFAD mouse are encouraging, they will establish predictive validity for the 5XFAD model, and warrant future research which may lead to the development of new pharmacological interventions for humans with AD.