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Role of ferroptosis of oligodendrocytes and vascular endothelial cells in vascular and Alzheimer's Disease related dementia

Award Number: RF1AG098171
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2030

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Role of ferroptosis of oligodendrocytes and vascular endothelial cells in vascular and Alzheimer's Disease related dementia - Project Summary Progress to define mechanisms of white matter injury (WMI) in vascular cognitive impairment and dementia (VCID) has been hampered by fundamental gaps in our understanding of glial mechanisms of remyelination failure, a hallmark of VCID. Progressive WMI is strongly associated with arteriolosclerosis mediated by chronic hypertension. Impaired reactivity of WM penetrating arterioles contributes to chronic microvascular ischemia, which in turn leads to blood brain barrier dysfunction, neuroinflammation, oxidative stress and dysregulation of extracellular matrix (ECM) signaling pathways. Together, these changes promote cognitive impairment from chronic WMI. We reported that during WMI, the hyaluronan (HA)-based ECM is disrupted in lesions where oligodendrocyte (OL) progenitor cells (OPCs) fail to differentiate to mature OLs. We also found that specific HA fragments generated by hyaluronidase activity block OPC maturation. Our preliminary findings support that the cell migration-inducing protein (CEMIP) hyaluronidase is elevated in aging WM vessels in association with perivascular depletion of HA. We propose to determine the role of CEMIP in the regulation of novel cell death pathways that disrupt vascular integrity and perivascular OPC survival and maturation. In human cases of VCID with Alzheimer's Disease (AD), we recently identified increased expression of key genes that contribute to WMI via ferroptosis, a form of programmed cell death involving iron overload and reactive oxygen species-dependent lipid peroxidation. Human brain vascular endothelial cells (BVECs) and OL lineage cells are susceptible to ferroptosis. Notably, recent studies suggest that high molecular weight forms of HA (HMW HA) can block ferroptosis through stabilization of the antiporter SLC7A11 via the HA receptor CD44. Our preliminary data suggest that HMW HA rescues human BVECs and OPCs from ferroptosis by inducing increased SLC7A11 expression, while CEMIP-digested HA loses this protective activity. Altogether, these findings support the overarching hypothesis that HA digestion by CEMIP enhances WMI through multiple complementary mechanisms that promote BVEC and OPCs ferroptosis. We propose to test the following hypotheses in our specific aims: (1) HA synthesis and catabolism are increased in WMI and HA digestion by hyaluronidase activity influences BVEC and OPC survival. (2) VCID and AD interact in vivo to accelerate WMI progression by enhancing microvascular CEMIP expression and HA metabolism, which promote BVEC ferroptosis, impaired microvascular reactivity and WMI. (3) Human OPCs accumulate at perivascular sites where CEMIP is elevated and display enhanced susceptibility to ferroptosis. Together, these studies will define novel HA-mediated mechanisms that regulate BVEC and OPC ferroptosis and will test novel strategies to block HA metabolism as potential targets to treat VCID.


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 = $3,401,351 )
2026	2026	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Aging Research	000	1	7/31/2026	NEW	$3,401,351
														Subtotal = $3,401,351

Grand Total All Awards = $3,401,351

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Role of ferroptosis of oligodendrocytes and vascular endothelial cells in vascular and Alzheimer's Disease related dementia

Award Number: RF1AG098171

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2030

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