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The Role of Peripheral Inflammation and APOE in Cerebrovascular Dysfunction in Alzheimer’s disease

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posted on 06.08.2019, 00:00 authored by Felecia M Marottoli
Apolipoprotein E4 (APOE4), amyloid-beta (A-beta), and peripheral inflammation (PI) are each independently associated with Alzheimer’s disease (AD) risk and progression. However, the mechanisms by which these factors exert their effects, both individually and in combination, has yet to be determined. Increasing evidence suggests that all of these factors may modulate the cerebrovasculature, which plays a critical role in maintaining neuronal homeostasis. Therefore, the goal of our research was to investigate the interaction of PI, APOE, and A-beta in inducing cerebrovascular dysfunction and, as an extension, cognitive decline. We initially demonstrated in vivo that the combination of APOE4, A-beta, and PI results in cerebrovascular damage including higher leakiness and lower vessel coverage. This cerebrovascular damage occurred concomitantly with cognitive deficits. We focused our in vitro studies on determining the role of PI and A-beta on disrupting brain endothelial cell (BEC) function, since published data on their effects lack consensus. A-beta and LPS induced lower vessel coverage and premature barrier decline in BECs. These data indicate that both of these AD-relevant stressors exert an effect directly on BECs. We next focused on dissecting the role of APOE in cerebrovascular dysfunction in vitro. In the brain, apoE is produced primarily by glia, however, the contribution of other cell types to APOE4-induced deficits remains unclear. Our novel data support that the APOE genotype of BECs modulates their function, possibly via isoform-specific differences in apoE autocrine and/or paracrine signaling. The deficits induced by APOE4 were much greater than those observed in wild-type BECs treated with A-beta and LPS. Thus, APOE4 may be the determining factor in predisposing the cerebrovasculature to damage in AD. Collectively, these data provide a basis to further dissect the interactions and mechanisms of PI, APOE, and A-beta in BEC function. Moreover, these findings identify BECs as a novel therapeutic target to treat AD risk factors.

History

Advisor

Tai, Leon

Chair

Brady, Scott

Department

Anatomy and Cell Biology

Degree Grantor

University of Illinois at Chicago

Degree Level

Doctoral

Committee Member

Simonovic, Miljan Yoshii, Akira Alford, Simon

Submitted date

May 2019

Issue date

19/03/2019

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