APOE4 and Brain Inflammation

As you probably know, there are no effective treatments that can modify or slow down the progression of Alzheimer’s Disease. It is necessary to have a new understanding of the key elements that are driving pathology and key targets that can be investigated to stop this disease and its effect on our aging population. 

Publication: Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4: cPLA2.

The Yassine Lab’s recent research identifies brain inflammation as a key target for drug development. The lab is working with colleagues at USC and internationally to identify drugs that can lower brain inflammation in the setting of APOE4. Inflammation increases the risk of cognitive decline and dementia in the brain. And APOE4 is associated with greater inflammation in the brain. The Yassine Lab looks at the mechanisms that allow Omega-3’s and fatty acids to exchange in the brain. Throughout a series of experiments over the past 5 years, Shaowei Wang, a postdoc in the Yassine Lab, identified that a specific enzyme known as cPLA2 or calcium-dependent phospholipase A2 is increased in APOE4 mouse models. This finding was later confirmed in a cohort of human brains that differ by APOE4 genotype. 

With collaboration from the Katritch lab, researchers landed on 3 potential candidates that effectively can block the great activation of cPLA2, verifying that information in vitro in the lab and by using cell models. To be able to identify which patients might benefit from such an intervention, researchers, Juno Van Valkenburgh and Marlon Duro developed an 18-F Arachidonic Acid PET probe in order to see the label by the scanner.  As you can see in the figure of the video, 18-F Arachidonic Acid uptake in the brain is shown in red in APOE4 targeted mice and correlated with brain inflammation. This could be a useful companion to identify patients with brain inflammation that would benefit from decreasing cPLA2 activity. 

What this paper tells us is that the excessive activation of cPLA2 liberates more arachidonic acid which is converted inside the cell into inflammatory mediators. Since cPLA2 liberates arachidonic acids from membranes, it drives brain inflammation. This means that cPLA2 could be a potential drug target and if greater activation is reduced, there can be an offset to brain inflammation. cPLA2 association with APOE4 is novel but has been shown before that strokes, and injuries to the spinal cord or to the brain such as traumatic brain injury activate cPLA2 and associate with a greater inflammatory signaling response. In this case, there was a subtle activation of cPLA2 and APOE4. Chronic subtle repetitive activation of cPLA2 over a long time can lead to a powerful inflammatory and oxidative stress response that cascades into disease. 

To learn more about this publication please visit https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-022-00549-5

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