Graduation Year

2024

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medicine

Major Professor

Lianchun Wang, Ph.D.

Committee Member

David Lominadze, Ph.D.

Committee Member

Gopal Thinakaran, Ph.D.

Committee Member

Mark Kindy, Ph.D.

Keywords

amyloid, cerebrovasculature, clearance, heparan sulfate, TREM2

Abstract

Alzheimer's disease (AD) is the most common form of dementia yet remains without an effective treatment due to its poorly understood etiology. Mounting evidence points to the accumulation and aggregation of amyloid-β peptides (Aβ), which constitute amyloid plaques in the brain, as pivotal in initiating and accelerating AD pathogenesis. Extensive efforts have focused on uncovering the molecular underpinnings and fundamental origins of impaired Aβ metabolism in AD. Heparan sulfate (HS), a linear polysaccharide of the glycosaminoglycan family, co-deposits with Aβ in plaques within the AD brain. It directly binds to and accelerates Aβ aggregation, interacts with key players in Aβ metabolism such as TREM2 and ApoE, and mediates Aβ internalization and cytotoxicity. Studies using AD mouse models demonstrate HS’s regulation of Aβ clearance and neuroinflammation in vivo. Given the impaired clearance of Aβ in sporadic AD, our research investigates vascular HS in Aβ clearance and the interaction of Aβ receptor TREM2 and HS. By examining cerebrovascular cells in human patients, we found an increased association of HS with Aβ in endothelial cell (EC) and vascular smooth muscle cell (vSMC) compartments and reversed HS polarization with high cerebrovascular Aβ burden. We also uncovered heightened vascular HS expression in female patients and re-affirmed increased Aβ in AD patients with ApoE4. To investigate HS-related Aβ clearance in the brain in vitro and in vivo, we manipulated cerebrovascular HS by targeting the Ext1 gene and observed diminished Aβ cellular internalization and perivascular drainage. Reduced EC-HS expression led to aggravated Aβ pathology and increased glial activation in 5xFAD and Tg-SwDI mouse models. Given TREM2’s role in binding to and modulating glial cells’ response to Aβ, as well as TREM2 mutations associated with AD, we examined the HS structural requirements to bind TREM2. We found that TREM2 binding to HS depends on HS size and specific sulfation modifications, requiring a minimum size of 9 saccharides and 6-O-sulfation. Overall, our findings significantly advanced understanding of the role of HS in AD pathogenesis and related mechanisms. In addition, our findings also hold significant implications, particularly in developing therapeutics targeting cerebrovascular Aβ clearance and neuroinflammation in AD. By selectively targeting cerebrovascular HS and HS-TREM2 interaction, we may unlock novel treatment pathways for AD and related diseases.

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