Wednesday, January 15, 2025 1/15/2025

Red Blood Cells shuttle beta amyloid between brain and heart: implications for the pathogenesis and the progression of Alzheimer's and Cardiomyopathy

Award Number: R01HL156116
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract Alzheimer disease (AD) is the most frequent form of dementia causing a significant reduction of quality of life of affected patients. In the brains of AD patients, β-amyloid (Aβ) was identified as the main component of the amyloid plaques. Recently, deposits of Aβ have been documented in peripheral organs in AD and we provided evidence that the heart is one of the affected organs. We and others, have also shown that the complement system has a critical, non-redundant roles in creating and maintaining a non-inflammatory intravascular environment by tagging and opsonizing circulating foreign or abnormally folded host proteins with C1q, MBL, C3b and C4b. Importantly, free Aβ42 binds 3 out of 4 CR1 (complement receptor 1) ligands namely C1q, C3b and C4b. In the presence of complement Aβ42, binds CR1 on circulating RBCs. Unique to RBCs, the expression levels of CR1 are genetically determined, with individuals expressing either 90 copies of CR1/RBC (L/low), 500 CR1 copies (HL/intermediate) or 1200 CR1 copies (H/high expressers). Recently, several reports using GWAS data, linked CR1 polymorphisms to an increased risk of late-onset AD, lending credence to the role for RBCs in AD pathogenesis. In AD patients an abnormal clearance in blood Aβ was recently suggested based on a shift in Aβ levels from liver to brain, heart and periphery. Based on these observations, the overall hypothesis of this application is that the genetically determined CR1 levels on circulating RBCs are critical in: a) binding and safely remove circulating Aβ and b) preventing the cell-free Aβ to translocate to the RBC cytosol and be delivered via exosomes to damage peripheral tissues such as the heart, leading to heart failure and, in turn, worsening AD. We will test and validate this hypothesis by: A) Investigating the role of RBC-CR1 levels in the distribution of Aβ in EVs, RBCs and free in blood. B) Defining the functional consequences of free vs. EVs bound Aβ shuttling between brain and heart using a lox-cre mouse model, and C) Validating the role of RBCs and EVs in AD pathogenesis using tissues samples from AD patients The results of this study support the future of use free and RBC-bound Aβ42 as biomarker reservoirs to stage disease progression and therapeutic progresses.


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: 2024 ( Subtotal = $488,028 )
2024	2024	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Blood Diseases and Resources Research	001	4	6/20/2024	NON-COMPETING CONTINUATION	$39,839
2024	2024	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Blood Diseases and Resources Research	000	4	1/10/2024	NON-COMPETING CONTINUATION	$448,189
														Subtotal = $488,028

Issue Date FY: 2023 ( Subtotal = $497,988 )
2023	2023	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Blood Diseases and Resources Research	000	3	1/25/2023	NON-COMPETING CONTINUATION	$497,988
														Subtotal = $497,988

Issue Date FY: 2022 ( Subtotal = $493,070 )
2022	2022	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Blood Diseases and Resources Research	001	2	6/15/2022	NON-COMPETING CONTINUATION	$49,308
2022	2022	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Blood Diseases and Resources Research	000	2	12/28/2021	NON-COMPETING CONTINUATION	$443,762
														Subtotal = $493,070

Issue Date FY: 2021 ( Subtotal = $502,136 )
2021	2021	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Blood Diseases and Resources Research	000	1	12/15/2020	NEW	$453,183
2021	2021	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Blood Diseases and Resources Research	001	1	7/28/2021	NEW	$48,953
														Subtotal = $502,136

Grand Total All Awards = $1,981,222

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Red Blood Cells shuttle beta amyloid between brain and heart: implications for the pathogenesis and the progression of Alzheimer's and Cardiomyopathy

Award Number: R01HL156116

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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