Friday, October 31, 2025 10/31/2025

Oxidation of K+ channels mediates an amyloidogenic pathway common to Alzheimer's disease and TBI

Award Number: R01AG060919
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Oxidation of K+ channels mediates an amyloidogenic pathway common to Alzheimer's disease and TBI - The voltage-gated potassium (K+) channel sub-family B member 1 (KCNB1) is susceptible to redox. As such oxidative modification of this channel has the potential to occur under, and consequently to impact, a number of conditions associated with oxidative stress. Accordingly, oxidized KCNB1 channels are present in the post mortem human hippocampi of aging donors and in significantly larger amounts in the hippocampi of Alzheimer's disease (AD) donors. KCNB1 oxidation increases neuronal loss and impairs cognitive function in mouse models of AD (3xTg-AD background) and traumatic brain injury (TBI). These two conditions are associated with multiple etiologies and pathogenic mechanisms but share robust oxidative stress. Moreover, the toxic effects associated with oxidation of the KCNB1 channels are moderated by Dasatinib, a FDA-approved drug. The broad goal of this proposal is to elucidate the molecular basis for the neurotoxic effects of KCNB1 oxidation. We will test two consequential hypotheses. First, that oxidized KCNB1 channels promote neurotoxicity through the Stress Activated Protein Kinase (SAPK) pathway. Second, that KCNB1-mediated activation of SAPK signaling provides a common amyloidogenic pathway in the AD and the TBI brains, by increasing b-amyloid production via direct and/or indirect dysregulation of the activities of the b-secretase (BACE1). We will test these hypotheses by the means of genetics, behavioral analysis, biochemistry and histochemistry. If successful, this work will: 1) advance our understanding of a widespread mechanism of neuronal vulnerability; 2) elucidate a new pathway for amyloidosis common to AD and TBI, that was not considered before and 3) may indicate novel therapeutic approaches that could be translated into clinical trials.


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: 2025 ( Subtotal = $0 )
2025	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Aging Research	000	5	4/9/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Aging Research	001	5	12/19/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$147,542
2024	2022	RUTGERS, THE STATE UNIVERSITY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Aging Research	000	4	12/19/2023	NON-COMPETING CONTINUATION	-$147,542
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $397,500 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Aging Research	001	5	2/3/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$397,500
2023	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Aging Research	000	4	2/3/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $397,500

Issue Date FY: 2022 ( Subtotal = $397,500 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Aging Research	000	4	11/30/2021	NON-COMPETING CONTINUATION	$357,750
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Aging Research	001	4	4/21/2022	NON-COMPETING CONTINUATION	$39,750
														Subtotal = $397,500

Issue Date FY: 2021 ( Subtotal = $397,500 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Aging Research	001	3	2/11/2021	NON-COMPETING CONTINUATION	$39,750
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Aging Research	000	3	12/10/2020	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $397,500

Issue Date FY: 2020 ( Subtotal = $397,500 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Aging Research	000	2	11/25/2019	NON-COMPETING CONTINUATION	$357,750
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Aging Research	001	2	1/23/2020	NON-COMPETING CONTINUATION	$39,750
														Subtotal = $397,500

Issue Date FY: 2019 ( Subtotal = $397,500 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Aging Research	000	1	1/28/2019	NEW	$397,500
														Subtotal = $397,500

Grand Total All Awards = $1,987,500

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Oxidation of K+ channels mediates an amyloidogenic pathway common to Alzheimer's disease and TBI

Award Number: R01AG060919

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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