The study revealed brain molecular changes associated with APOE4, the main susceptibility gene for Alzheimer's disease

Recent breakthroughs have revealed a lot of information about Alzheimer's disease, but researchers have yet to paint a complete picture
of how the genetic risk of the disease leads to brain damage, ultimately leading to memory loss and cognitive decline.

A new study from the Keck School of Medicine of USC, just published in the Journal of Experimental Medicine, adds a key link
to the puzzle.

The study was published in the Journal of Experimental Medicine on August 30, 2022 (latest impact factor: 17.

APOE4 is a variant of the apolipoprotein E gene that has been well demonstrated
for its strong risk of developing Alzheimer's disease.

"There is currently no large-scale comprehensive molecular analysis to understand how the APOE4 gene affects blood vessels associated with brain function," said the study's lead author, Dr.

Zlokovic and his colleagues studied mouse brains at the molecular level, and they found that APOE4 first causes problems with blood-brain barrier cells, then triggers problems with synapses (the structures that allow brain cells to communicate), and ultimately leads to behavioral deficits and cognitive dysfunction
.

Zlokovic said: "Understanding the sequence of events (what happened first and what happened later) is very valuable, because the relationship between
changes in the blood-brain barrier and synaptic dysfunction has not been shown at the molecular level.

Zilkha Institute of Neurogenetics

To investigate the effects of the APOE4 gene on the brain, the researchers studied gene "knock-in" mice, replacing the APOE gene of the mouse with a human APOE gene variant
.

A comprehensive picture of what's happening inside a cell requires a combination of cutting-edge analytical techniques
.

In mice carrying the APOE4 gene, the team first detected damage
to endothelial and peripheral cells.

Zlokovic said: "When synaptic function is still normal, we found this gradual decline
in blood-brain barrier cells.

Within two to five months, the researchers found that synaptic signals between brain cells were interrupted
.

APOE4 and the blood-brain barrier (not pictured in this study article)

Target cells and proteins

Since this study reveals multiple mechanisms by which the APOE4 gene causes brain damage, it also points to several potential pathways
that future treatments can target.

One approach is to try to protect and strengthen the network of proteins within the blood-brain barrier, which may make the blood-brain barrier healthier
.

Both genetic and proteomic data from the study are now publicly available for other researchers to explore and analyze, which could reveal the possibility of
further treatment.

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