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Exploring glycan-protein interactions at the blood-brain barrier in cerebral amyloid angiopathy

Award Number: R01AG102717
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/16/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Exploring glycan-protein interactions at the blood-brain barrier in cerebral amyloid angiopathy - Abstract Cerebral amyloid angiopathy (CAA) is the most common vascular comorbidity in Alzheimer’s disease (AD), and impaired perivascular clearance of amyloid beta (Aβ) is known to be a key driver of CAA onset and progression. An important, yet understudied facet of Aβ clearance in CAA is the change in sugar composition on the surface of the brain endothelial cell (BEC). Chondroitin sulfate (CS) glycosaminoglycans coat the BEC matrix with long, anionic chains of repeating disaccharide units that can be differentially sulfated to modulate interactions with proteins, such as Aβ. While altered brain CS sulfation has been strongly associated with AD, the impact of altered BEC CS sulfation on perivascular Aβ clearance in CAA has yet to be evaluated. This proposal posits that AD- related changes in CS sulfation on the BEC surface promotes perivascular Aβ accumulation, thereby driving the CAA pathogenesis. Although FDA-approved drugs targeting Aβ have shown success in treating cognitive impairment for patients with early-stage AD, the use of these anti-Aβ drugs for CAA is strongly discouraged due to cerebrovascular complications. As such, a dire need exists to develop alternative treatments aimed at reducing the clinical burden of CAA, whilst maintaining cerebrovascular integrity. CS hypersulfation has been reported in human AD brain tissue, as measured by liquid chromatography tandem mass spectrometry (LC-MSMS). Detailed description of CS composition at the cellular level has thus far been limited by the non-specificity and constrained sensitivity of traditional histochemical approaches. Leveraging highly specific and sensitive LC- MSMS methods that enable robust quantification of CS sulfation, this project will, for the first time, comprehensively profile CS glycans on BECs isolated from human brain tissue with confirmed CAA pathology. Preliminary Data show that BECs isolated from human AD brain tissue exhibit CS hypersulfation, compared to brain tissue from non-demented controls. The Central Hypothesis of this proposal is that CS hypersulfation augments perivascular Aβ accumulation and contributes, in part, to the onset and progression of CAA. To test our central hypothesis and define the role of BEC CS sulfation in CAA, this proposal will 1) combine human BEC isolations with LC-MSMS analysis of CS sulfation patterns and Aβ binding kinetics (SA1), will 2) assess a preclinical CAA phenotype after experimentally manipulating CS sulfation (SA2), and will 3) explore CS sulfation as a mechanism of Aβ clearance using an in vitro model of the human blood-brain barrier (SA3). Successful completion of this proposal will have established innovative LC-MSMS methods to identify CS sulfation patterns on mammalian BECs to be strongly associated with CAA-related pathology. It is expected that the successful completion of this project will showcase an underappreciated pathway in the CAA pathogenesis and identify CS suflation as a novel therapeutic target to enhance perivascular Aβ clearance and improve cognition. Collectively, these outcomes are expected to have an important positive impact because they will provide fundamental new knowledge of the mechanisms underlying CAA and lay the groundwork for CS glycan-targeted interventions.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $680,689 )
2026	2026	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH ST	LUBBOCK	TX	79430	LUBBOCK	USA	Aging Research	000	1	9/16/2026	NEW	$680,689
														Subtotal = $680,689

Grand Total All Awards = $680,689

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Exploring glycan-protein interactions at the blood-brain barrier in cerebral amyloid angiopathy

Award Number: R01AG102717

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/16/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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