New study links DEK protein to nerve cell dysfunction in Alzheimer's disease

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What does your post show?

We study neurons that are particularly vulnerable to Alzheimer's disease, because they deteriorate very early in the course of the disease. In these neurons, we showed that low levels of DEK, with a previously unknown function, lead to changes in neuronal activity and to the accumulation of tau protein, which is a hallmark of Alzheimer's disease pathology. This effect is accompanied by the reaction of immune cells in the brain and the loss of these neurons, say the corresponding authors Patricia Rodriguez RodriguezSenior Research Specialist in the Department of Neuro-Aging Diseases, Department of Neuroscience, Health Sciences and Society.

Why are results important?

In Alzheimer's disease, certain groups of nerve cells within certain areas of the brain deteriorate years before patients develop symptoms. The reasons for the weakness of these nerve cells are unknown and may be key to developing treatments aimed at treating the disease in its early stages, when they are most effective. The current study identifies a new factor that causes pathological changes in these neurons and sheds light on pathways that contribute to early neurodegeneration in Alzheimer's disease.

How was the study conducted?

– In collaboration with leading experts in computational genomics from Rice University and with co-author Dr. Jean-Pierre Roseri (Boston University), we used a new computer-based method to predict driver factors for Alzheimer's disease (Neuron, 2020). This approach helped us identify, in a fully data-driven manner, the DEK protein as a potential driver of Alzheimer's pathology. Because its function in the brain was not known, we normalized its levels in vulnerable Alzheimer's neurons in mouse models and cells in culture. This helped us study how their gain or loss of function affected the biology of these neurons and whether they caused pathological changes.

What's the next step in your research?

-We will focus on understanding how DEK function is affected by various Alzheimer's disease etiologies and risk factors, and whether modulating this protein and/or its associated pathways can prevent disease progression. We will also look at how a genetic mutation in its genes affects its function and affects the onset and progression of the disease in the population that carries it.

Publishing

A cell-autonomous regulator of neuronal excitability modulates tau in neurons susceptible to Alzheimer's disease.
Rodriguez Rodriguez P, Arroyo-Garcia LE, Tsagkogianni C, Li L, Wang W, Végvári Á, Salas-Allende I, Plautz Z, Cedazo-Minguez A, Sinha SC, Troyanskaya O, Flajolet M, Yao V, Roussarie JP, brain, Online 11 March 2024.