Characterization of Alzheimer's disease‐like neuropathology in Duchenne's muscular dystrophy using the DBA/2J mdx mouse model

Abstract

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder caused by a mutation in the dystrophin gene. In addition to muscle pathology, some patients with DMD will exhibit cognitive impairments with severity being linked to age and type of genetic mutation. Likewise, some studies have shown that mdx mice display impairments in spatial memory compared with wild‐type (WT) controls, while others have not observed any such effect. Most studies have utilized the traditional C57BL/10 (C57) mdx mouse, which exhibits a mild disease phenotype. Recently, the DBA/2J (D2) mdx mouse has emerged as a more severe and perhaps clinically relevant DMD model; however, studies examining cognitive function in these mice are limited. Thus, in this study we examined cognitive function in age‐matched C57 and D2 mdx mice along with their respective WT controls. Our findings show that 8‐ to 12‐week‐old C57 mdx mice did not display any differences in exploration time when challenged with a novel object recognition test. Conversely, age‐matched D2 mdx mice spent less time exploring objects in total as a well as less time exploring the novel object, suggestive of impaired recognition memory. Biochemical analyses of the D2 mdx brain revealed higher soluble amyloid precursor protein β (APPβ) and APP in the prefrontal cortex of mdx mice compared with WT, and lower soluble APPα in the hippocampus, suggestive of a shift towards amyloidogenesis and a similar pathogenesis to Alzheimer's disease. Furthermore, our study demonstrates the utility of the D2 mdx model in studying cognitive impairment.

The effects of neurogranin knockdown on SERCA pump efficiency in soleus muscles of female mice fed a high fat diet

“…The novel object recognition test was performed as described in detail by Hayward etal. ( 28 ). Briefly, mice were allowed to freely explore an empty arena (40x40x40 cm) for 10minthe day prior to testing in a prehabituation period.…”

Kynurenine metabolism is altered in mdx mice: a potential muscle to brain connection

“…It is expected that memory-intact rodents will explore a novel object for longer durations than a familiar object, while memory-impaired rodents will have no preference for either object, exploring both for similar durations (Ennaceur and Delacour 1988). In a recent study with the same mice used in this study, it was found that D2 mdx mice had significant memory deficits compared to their WT counterparts with significantly lower exploration time (Hayward et al 2021). However, this was not observed in age-matched C57 mdx mice and we believe that this corresponds to the known differences in disease severity between the strains of mice (Coley et al 2016;Hammers et al 2020;van Putten et al 2019).…”

“…Videos were examined manually by a blind experimenter for exploration of novel and familiar objects, total movement time, and time spent in corners. The exploration times were reduced only in the D2 mdx mouse and was not due to differences in time spent moving between the C57 and D2 mdx mice (Hayward et al 2022). However, further analysis of specific locations during mice movement was not analyzed.…”

“…A novel object recognition test (NORT) was performed in an arena containing four equal sized, open top boxes, over three 10 minute phases: acclimatization, training, and testing (Hayward et al 2022). Pilot testing during the acclimation period indicated no preference to any specific locations within each box.…”

Kynurenine metabolism is altered in mdx mice: a potential muscle to brain connection

“…A novel object recognition test (NORT) was performed in mice by the time they were 9–10 weeks of age in an arena containing four equal sized open top boxes, over three 10 min phases: acclimatization, training and testing (Hayward et al., 2022). Pilot testing during the acclimation period indicated no preference to any specific locations within each box.…”