Zilkha Seminar Series: Joel Blanchard PhD - "Reconstruction of the Human Blood-Brain Barrier in vitro reveals a Pathogenic Mechanism of APOE4 in Pericytes"

Wednesday, October 16 at 12:00pm to 1:00pm

This is a past event.

Zilkha Neurogenetic Institute (ZNI), 112
1501 San Pablo, Los Angeles, CA 90033

The majority of Alzheimer’s disease patients and 20–40% of non-demented elderly experience amyloid deposits along their cerebral vasculature, a condition known as cerebral amyloid angiopathy (CAA). CAA impairs the function of the blood-brain barrier (BBB) leading to ischemia, hemorrhages, and accelerated cognitive dysfunction. The APOE4 allele is the strongest known risk factor for CAA and sporadic Alzheimer’s disease (AD).

However, the pathogenic mechanisms underlying this predisposition are unknown. Here, we recreate the human BBB in vitro by co-culturing iPSC-derived, brain endothelial cells, pericytes, and astrocytes in 3D scaffolding to construct a highly tractable model that recapitulates key anatomical and physiological properties of the BBB. Similar to the human brain, we find amyloid accumulates on our in vitro BBB (iBBB) and both APOE4 homozygous and heterozygous iBBBs exhibit significantly more amyloid accumulation than APOE3/3 iBBBs. We then use reciprocal isogenic iPSC-derived iBBBs to dissect the mechanisms underlying APOE4 predisposition to cerebrovascular amyloid accumulation.

Through combinatorial experiments, we pinpoint that pericytes have a causal role in the development of CAA. We discover that APOE expression is markedly up-regulated in APOE4 pericytes and causally linked to increased vascular amyloid accumulation. Transcriptional profiling subsequently revealed that calcineurin/NFAT signaling is dysregulated in APOE4 pericytes. In the post-mortem human brain, we also found that APOE and NFAT are significantly elevated in pericytes of APOE4-carriers compared to non-carriers. Pharmacologically inhibiting calcineurin down-regulated APOE expression in pericytes to comparable levels observed in APOE3 pericytes and remarkably decreased amyloid deposition in APOE4 iBBBs in vitro and APOE4 knock-in AD mice in vivo. These results demonstrate an unexpected role of pericytes in cerebral amyloid deposition and advocate that inhibiting calcineurin/NFAT-signaling could be a therapeutic strategy to mitigate APOE4 predisposition to CAA and potentially AD. 

Event Type

Lecture / Talk / Workshop

Audience

Students, Alumni, Faculty/Staff

Campus

Health Sciences Campus

Department
Keck School of Medicine
Add this to your calendar

Recent Activity