Alzheimer’s-like Brain Features Found in Mouse Model of Severe DMD

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Cognitive problems seen in some Duchenne muscular dystrophy (DMD) patients may be associated with a shift toward the amyloidogenic pathway in memory-specific brain regions, according to a study in mouse models of the disease.

The amyloidogenic pathway is a signaling cascade that leads to the formation of beta-amyloid, the molecule responsible for the buildup of toxic plaques in the brains of people with Alzheimer’s disease.

Memory deficits were observed in a mouse model of severe DMD, but not in a model of milder disease, further emphasizing the utility of the severe DMD model in studying cognitive impairment and other potential features of this disease.

Further studies are needed to confirm a link between this molecular shift and cognitive deficits, as well as to better understand the mechanisms behind it, the researchers noted.

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The study, “Characterization of Alzheimer’s disease-like neuropathology in Duchenne’s muscular dystrophy using the DBA/2J mdx mouse model,” was published in the journal FEBS Open Bio.

DMD is caused by the loss of dystrophin, a key protein for muscle strength, due to mutations in the DMD gene. Dystrophin is also present in nerve cells and has been found in memory-related brain regions, suggesting a role in brain function.

In addition to the disease’s hallmark muscle wasting, some DMD patients develop cognitive problems, “with severity being linked to age and type of genetic mutation,” the researchers wrote.

However, the underlying molecular mechanisms of these cognitive deficits remain unclear.

A previous study showed that DMD patients have significantly higher levels of the beta-amyloid protein in the blood compared with healthy people and that higher beta-amyloid levels were significantly associated with lower IQ, or greater cognitive impairment.

The accumulation of toxic clumps of beta-amyloid in the brain is the main hallmark of neurodegeneration in Alzheimer’s disease, a condition characterized by progressive learning and memory problems and the most common cause of dementia.

Amyloid-beta is derived from the amyloid precursor protein (APP) through the amyloidogenic pathway. This pathway is dependent on the BACE1 enzyme, and it first leads to the formation of a soluble APP-beta fragment that is subsequently cleaved further to generate amyloid-beta.

APP can also be broken down through a nonamyloidogenic pathway, which results in the generation of a soluble AAP-alpha fragment that does not form toxic clumps and is thought to have neuroprotective properties.

To gain insight on a potential link between cognitive impairment and amyloid-related molecules in DMD, researchers in Canada examined the brains of two mouse models of the disease.

One model, called C57BL/10 mdx, is the most commonly used mouse model in DMD studies and exhibits a milder disease relative to DMD patients. The other, more recent model, called DBA/2J mdx, shows more severe disease and an earlier onset, “making it a more viable model to study muscular dystrophy,” the researchers wrote.

The difference between these models lies in their genetic background.

The team first evaluated the memory performance of these DMD models against their respective controls (healthy mice with the same genetic background) using the novel object recognition test. The test is based on rodents’ preference to explore new objects.

All mice were evaluated at the same age.

Results showed that both mice with milder DMD-like disease and their healthy controls explored the new object for a longer time than familiar objects, with no significant differences between the groups. This was consistent with data from some previous studies, the team noted.

In contrast, mice with more severe disease spent significantly less total time exploring objects and less time exploring the new object compared with their control mice, suggesting impaired recognition memory.

Given that cognitive impairment was only observed in mice with more severe DMD-like disease, the team focused on this model in subsequent analyses of amyloid-related proteins and markers of synapses. Synapses are the sites of transmission of chemical messengers and electrical signals between nerve cells.

Such analyses revealed that these mice had significant changes in the levels of APP, APP-beta, and APP-alpha in memory-related brain regions (prefrontal cortex and hippocampus) relative to healthy mice.

Particularly, APP and APP-beta levels were significantly higher, and APP-alpha levels were numerically, but not significantly, lower in the prefrontal cortex of the mouse model. In the hippocampus, APP-alpha was significantly reduced, while APP and APP-beta showed no changes.

Both brain regions of mice with severe DMD-like disease showed a lower APP-alpha/APP-beta ratio relative to healthy mice, suggesting “a shift towards the amyloidogenic pathway” and “a similar [molecular mechanism] to Alzheimer’s disease,” the researchers wrote.

Ratio differences between groups only reached statistical significance for the prefrontal cortex.

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No differences in the levels of BACE1 were detected between affected and healthy mice. Further studies on its enzymatic activity are needed to better understand changes in amyloid-related proteins and its potential link with dystrophin, the team noted.

Interestingly, the levels of a synaptic marker called PSD-95 were significantly increased in the prefrontal cortex of mice with severe disease, compared with their healthy controls.

While this finding is consistent with a previous study, “the mechanism behind this increase in postsynaptic markers remains elusive,” the team wrote, adding that “future research should aim to further elucidate this mechanism and examine functional changes to synaptic signalling.”

Together, these findings highlight that DMD “is not only associated with elevated circulating [amyloid-beta], but brain dystrophin loss is associated with a shift towards the amyloidogenic pathway in memory-specific brain regions of mdx mice,” the researchers wrote.

They also provide “further explanation for cognitive dysfunction and memory impairments seen in patients with DMD” and support the use of this mouse model of severe DMD “to inform on other potential mechanisms or therapeutic strategies that could potentially apply to human DMD,” the team concluded.