Cellular Messages Misplaced in Alzheimer's Disease

Researchers at the Francis Crick Institute and UCL have shown that genetic messages are misplaced in nerve cells in a model of Alzheimer’s disease and frontotemporal dementia.

These messages mostly affect the function of the mitochondria, the cell’s energy producers, and can be re-established using a drug currently in clinical trials.

Genetic messages or transcripts called mRNAs deliver instructions to make proteins from the DNA in the nucleus. Researchers at the Crick previously identified that some mRNAs are found in the wrong place in neurons with genetic mutations that cause motor neuron disease (MND).

In research published today in Cell Reports, the team aimed to understand whether this misplacement also occurs in two major types of dementia, Alzheimer’s disease and frontotemporal dementia (FTD).

They took skin cells from people with inherited forms of Alzheimer’s disease or FTD who had mutations in APP or PSEN1 genes (Alzheimer’s disease) and VCP (FTD). These cells were then ‘transformed’ back into a stem cell state and then carefully specialised into cortical neurons, found in the cortex of the brain. These were compared to cortical neurons developed from stem cells from healthy donors.

The researchers then split the cells into the nucleus (the main compartment containing the DNA, although some DNA is also contained within the cellular batteries called mitochondria that reside outside of the nucleus) and the cytoplasm (the rest of the cell) and mapped all the mRNA transcript locations. In the control neurons, the locations of the transcripts matched a dataset of over 4,000 mRNAs known to be typically found in either the nucleus or the cytoplasm, meaning they were in the correct locations.

But this was not the case in the neurons with the neurodegenerative mutations: between 82 and 140 mRNAs were found in a different place depending on the type of mutation. There were ten commonly misplaced mRNAs across Alzheimer’s disease and FTD – one was relocated to the nucleus and nine to the cytoplasm, and all were found to carry messages from genes related to mitochondrial function.

The team next looked at postmortem tissue from 40 people with FTD and 49 healthy donors. Four out of the nine identified misplaced mRNAs were significantly associated with worse disease outcomes and were clear markers of disease.

Dialling down the cell’s power sources

Because RNAs from mitochondria were also consistently misplaced, the team next investigated changes to DNA inside the mitochondria which gives them specific instructions, known as mitochondrial DNA. 

They recorded significant amounts of this type of DNA outside of the mitochondria, suggesting that both mRNAs and DNA were leaking out of the mitochondria.

They also observed that diseased neurons had fewer mitochondria overall and these were smaller in size and produced less energy. Mitochondrial DNA that had leaked into the cytoplasm also switched on a pathway involved in inflammation in the brain, which the researchers believe could be linked to some neurodegenerative symptoms.

Restoring order

Finally, the team treated the diseased cells with a drug called ML240, which inhibits a particular function of the VCP protein.

Treatment with this drug returned the misplaced mRNAs to their typical locations. It also extended its effects to the mitochondria, reducing the amount of mitochondrial DNA leakage, preventing inflammatory pathways and raising mitochondrial activity back to normal levels.

Christy Hung, former Race Against Dementia Fellow and Alzheimer’s Research UK Senior Fellow in the Human Stem Cells and Neurodegeneration Laboratory at the Crick and now Herbalgy Presidential Associate Professor at the City University of Hong Kong, said: “We have identified a common phenomenon in types of dementia and motor neurone disease: the messages carrying instructions from the DNA are ending up in different places, affecting cell functions.

“The effects on the mitochondria, such as leakage of mitochondrial DNA, which then triggers inflammation, may even be a universal mechanism in neurodegeneration.”

Rickie Patani, Senior Group Leader of the Human Stem Cells and Neurodegeneration Laboratory at the Crick, professor at UCL and consultant neurologist at the National Hospital for Neurology, said: “There is a desperate and unmet need to understand fundamental molecular mechanisms underlying Alzheimer’s disease and FTD. Our findings suggest that  misplacement of genetic building blocks like mRNA and mitochondrial DNA could be a common mechanism that is potentially therapeutically tractable. The next step is to test whether VCP inhibitors work in model organisms and also whether this misplacement of  genetic building blocks happens in sporadic forms of disease.”

Reference: Hung C, Llorian M, Pal K, et al. Mislocalization of nucleic acids is a convergent and targetable mechanism in Alzheimer’s disease and frontotemporal dementia. Cell Reports. 2025;44(7):115867. doi: 10.1016/j.celrep.2025.115867

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