Age‐related deterioration of motor function in male and female 5xFAD mice from 3 to 16 months of age

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to age‐related cognitive and sensori‐motor dysfunction. There is an increased understanding that motor dysfunction contributes to overall AD severity, and a need to ameliorate these impairments. The 5xFAD mouse develops the neuropathology, cognitive and motor impairments observed in AD, and thus may be a valuable animal model to study motor deficits in AD. Therefore, we assessed age‐related changes in motor ability of male and female 5xFAD mice from 3 to 16 months of age, using a battery of behavioral tests. At 9‐10 months, 5xFAD mice showed reduced body weight, reduced rearing in the open‐field and impaired performance on the rotarod compared to wild‐type controls. At 12‐13 months, 5xFAD mice showed reduced locomotor activity on the open‐field, and impaired balance on the balance beam. At 15‐16 months, impairments were also seen in grip strength. Although sex differences were observed at specific ages, the development of motor dysfunction was similar in male and female mice. Given the 5xFAD mouse is commonly on a C57BL/6 × SJL hybrid background, a subset of mice may be homozygous recessive for the Dysf im mutant allele, which leads to muscular weakness in SJL mice and may exacerbate motor dysfunction. We found small effects of Dysf im on motor function, suggesting that Dysf im contributes little to motor dysfunction in 5xFAD mice. We conclude that the 5xFAD mouse may be a useful model to study mechanisms that produce motor dysfunction in AD, and to assess the efficacy of therapeutics on ameliorating motor impairment.

Whisker exploration behaviours in the 5xFAD mouse are affected by sex and retinal degeneration

“…These behaviours are all associated with an increase in controlled and focussed exploration of an object. 30,33 No motor phenotype has previously been documented in 5xFAD mice at 6 to 7 months of age, [17][18][19] therefore, these differences in exploratory whisker movements may be due to cognitive or emotional (ie, anxiety) differences between the transgenic and WT mice. However, although not directly measured here, we did not notice any stress or anxiety-like behaviours in any of the mice.…”

“…13 Behaviourally, the 5xFAD mice have memory impairments, showed by a lack of recognition for novel objects at 6 to 7 months of age 14 and spatial memory deficits. 15,16 They also have motor impairments after 9 months of age, [17][18][19] age-related deafness 20 and social impairments 11 from 12 months of age. The 5xFAD mice also show a reduction of inhibitory interneurons in Layer IV of the whisker barrel cortex, which leads to changes in vibrissae-related behaviour that include a lack of whisker barbering in the home cage and an avoidance of enclosed spaces, which dissipates when the whiskers are trimmed.…”

Sex differences in mechanisms of disease

“…Characterization of behavioral phenotypes in female genetic models will, therefore, be a critical step in determining their utility for understanding sex‐dependent AD symptoms and disease trajectories. An extensive battery of locomotor behavior across the adult lifespan (age 3‐16 months) showed that, despite robust motor deficits in 5xFAD mice of both sexes and a few age‐dependent sex differences, very few sex × genotype interactions could be observed . Along similar lines, Grant et al found that whisking behavior in several exploratory tasks depended more on sex and the presence of retinal degeneration than on the 5xFAD genotype itself.…”

Genetic background modifies CNS‐mediated sensorimotor decline in the AD‐BXD mouse model of genetic diversity in Alzheimer's disease

“…Significant progress in understanding the pathophysiology of AD has been made using mouse models incorporating familial mutations in amyloid precursor protein ( APP ) and/or presenilin‐1 ( PSEN1 ), originally designed to recapitulate the cognitive symptoms of AD. Notably, several of these models have been reported to also exhibit sensorimotor deficits, suggesting that motor impairments are an inherent part of the disease process . However, infrequent assessment of motor phenotypes in AD animal models, variability in the tests used to assess motor function, and use of a single sex has led to conflicting reports on the impact of AD transgenes on motor function …”

“…Notably, several of these models have been reported to also exhibit sensorimotor deficits, suggesting that motor impairments are an inherent part of the disease process. [7][8][9][10][11][12][13] However, infrequent assessment of motor phenotypes in AD animal models, variability in the tests used to assess motor function, and use of a single sex has led to conflicting reports on the impact of AD transgenes on motor function. 7,10,11,14,15 The etiology of AD in humans is complex and although age is the greatest risk factor for developing AD, it is increasingly clear that genetics and family history play a significant role.…”