TDP-43 dysfunction in brain blood vessels may drive Alzheimer’s and ALS progression

Reduced levels of a critical protein are linked to devastating brain diseases such as Alzheimer’s, frontotemporal dementia and amyotrophe lateral sclerosis (ALS). Surprisingly, the protein deficiency mainly influences the blood vessels of the brain.

Researchers from the University of Connecticut report in the number of April 16 of Science is progressing Those mutations in the TardBP Gen that the TDP-43 protein levels are leaving, the cells that finish blood vessels in the brain also influence. They are called endothelial cells and play a crucial role in maintaining the blood-brain barrier, a protective shield that prevents harmful substances from entering the brain. When endothelial cells miss sufficient TDP-43 protein, they do not stay so tight together. This creates openings in the blood vessel walls, so that large or toxic molecules can leak in the brain. The resulting damage can play a role in the progression of neurodegenerative diseases such as Alzheimer’s, frontotemporal dementia and ALS.

To view this better, the researchers used a mouse model with a TardBP Mutation that is known to be associated with both and frontotemporal dementia. They also used a second model with genetically modified mice that only removed the TDP-43 protein from endothelial cells, not other cells in the brain. Both mouse models showed clear signs of breakdown blood-brain barrier, brain inflammation and behavioral shortages. This contributes to the growing amount of evidence that the defects in TDP-43 are being observed for the first time in neurons of patients with ALS and frontotemporal dementia are also found in other cells of the brain. This can explain the varied presentations of these diseases. As is mainly defined by increasing paralysis, while frontotemporal dementia contains cognitive impairment. But in many cases the two overlap. Insight into cell type specific vulnerabilities will probably provide answers to the complex human presentations of these diseases. It can also shed light on less genetically linked diseases, such as Alzheimer’s, where TDP-43 DIS function is also observed.

And although genetic mutations seem to play a role in some of these devastating brain diseases, they do not tell the whole story.

“While some people with ALS or Frontotemporal dementia wear mutations in the TDP-43 protein, most patients are not yet becoming protein in almost all cases still dysfunctional. This tells us that other unknown factors in the body can cause TDP-43 dysfunction“Says School of Medicine researcher Ashok Chemala.”In the next phase of our research, we want to understand what TDP-43 DIS function in endothelial cells in the absence of mutations in the gene. “Chemala and Uconn School of Medicine biologist Patrick Murphy and their colleagues are working on finding other genes that can limit TDP-43 disk function. Some of them can offer new approaches to limit or delay the progress of these diseases.

The team also tests whether TDP-43 DIS function can spread between the endothelium and other cells in the brain. Brainbloed vessels have constant contact with neurons and support cells such as astrocytes. When TDP-43 becomes dysfunctional, the lumps and these lumps can spread between cells. The researchers have shown that endothelial TDP-43 disk function takes place early in the disease. This suggests that abnormal TDP-43 may be able to infect adjacent cells in a chain reaction.

“By discovering how TDP-43 becomes harmful and spreads, we hope to discover new ways to protect the brain, maintain the blood-brain barrier and to stop the progression of diseases such as as, frontotemporal dementia and alzheimer“Says Murphy.