CHARACTERIZATION OF AGE-RELATED CHANGES IN MOTOR ABILITY AND LEARNING AND MEMORY IN THE 5XFAD MOUSE MODEL OF ALZHEIMER’S DISEASE

Abstract

The 5XFAD mouse is a double transgenic model of Alzheimer’s disease (AD), which harbors a human amyloid precursor protein transgene with three mutations (K670N/M671L, I716V, V717I) and a human presenilin-1 transgene with two mutations (M146L, L286V). These mutations act additively to produce large amounts of amyloid-beta (A?) and rapid development of AD-related pathology, including A?-plaques, neuroinflammation, synapse loss, impaired synaptic plasticity and death of layer 5 cortical neurons (Oakley et al., 2006, J. Neurosci., 26, 10129-10140). Despite the extensive characterization of neuropathology in the 5XFAD mouse, much less research has been completed characterizing age-related changes in behaviour. Sex, the albinism producing tyrosinase mutation (Tyrc), the retinal degeneration phosphodiesterase 6b mutation (Pde6brd1) and the limb-girdle muscular dystrophy 2B dysferlin mutation (Dysfim) are genetic factors present in the background strain (C57BLxSJL) of the 5XFAD mouse and other AD models. However, background genetic factors are rarely controlled, and their influence on AD-related behavioral phenotypes is largely unknown. Therefore, the objectives of this thesis were to characterize age-related changes in behaviour of the 5XFAD mouse, and determine the extent to which background genetic factors influence the expression of AD-related behavioral phenotypes. Male and female 5XFAD and wild-type (WT; C57BL6xSJL F2) mice completed a behavioural test battery at 3-4, 6-7, 9-10, 12-13 and 15-16 months of age in a cross-sectional experimental design. In experiment 1, motor ability was assessed with the open-field (locomotor activity), rota-rod (motor coordination and learning), balance beam (balance) and the wire and grid suspension tests (grip-strength). 5XFAD mice weighed less than WT mice at 9-15 months of age, and also reared less on the open-field and performed worse on the rota-rod. 5xFAD mice also travelled less distance on the open-field, fell faster on the balance beam and showed impaired grip-strength at 12-13 months of age. The Dysfim mutation has been previously shown to produce muscular weakness and impair motor function, but mutant Dysfim did not impair the motor performance of either WT or 5XFAD mice. In experiment 2, 5XFAD and WT mice were tested on the Morris water maze to assess visuo-spatial learning and memory. 5XFAD mice were impaired in acquisition and reversal learning, but not memory at 6 and 9 months of age. Motor impairments in 5XFAD mice impaired swimming ability and confounded learning and memory performance of mice at 12 and 15 months. Female mice performed worse than male mice, and albino mice performed worse than pigmented mice, demonstrating that background genetic factors influence the performance of mice on the Morris water maze. In experiment 3, olfactory learning and memory was assessed with an olfactory digging discrimination test. 5XFAD mice did not differ from WT mice in memory performance at any age tested. We then examined A? plaque pathology in 5XFAD mice and confirmed the presence of A? deposits in brain regions associated with motor function and learning and memory. Very few A? deposits were present in the cerebellum suggesting plaque pathology in the basal ganglia and/or motor cortex impairs motor function. Extensive A? plaque deposition was also found in the olfactory memory system despite the lack of olfactory memory impairment in 5XFAD mice. These results indicate that the 5XFAD mouse is a useful model for A?-pathology, cognitive and motor impairments observed in AD, but it is required that sex and albinism are properly controlled in the assessment of cognitive function.