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The effects of APOE4 on carnitine/acylcarnitine mediated bioenergetic deficits in Alzheimer's disease

Award Number: R03AG070540
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2021
PERIOD OF PERFORMANCE END DATE: 02/29/2024

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The effects of APOE4 on carnitine/acylcarnitine mediated bioenergetic deficits in Alzheimer's disease - Alzheimer’s disease is a neurodegenerative condition which affects 50 million people worldwide. It is increasing being recognized that, in addition to amyloid and tau, there are other factors which contribute to the complex and heterogenous etiology of AD. In that regard, recent investigations show that brain bioenergetic deficits and abnormal lipid metabolism alter the brain’s milieu, making it more susceptible to age-related insults and thereby increasing the brain’s vulnerability to developing AD. Carnitine and acylcarnitines are critical for central nervous system (CNS) bioenergetics due to their role in fatty acids oxidation in mitochondria for the brain’s energy requirements. Bioenergetic deficits are observed at an early age in subjects with the apolipoprotein E (APOE) ε4 allele, which is the most important genetic risk factor for majority of late-onset AD cases. The proposed work will explore the influence of APOE ε4 in carnitine- and acylcarnitine-mediated bioenergetic deficits in the pathogenesis of AD. We recently observed that carnitine, a carnitine metabolite trimethylamine N-oxide (TMAO) and acylcarnitine levels are altered in the blood and brains of AD patients. We also show that ε4 carriers at preclinical or early stages of AD have elevated levels of TMAO. Elevated medium chain acylcarnitine (MCA) were detected in the brain and blood of ε4 carriers, reflecting an incomplete fatty acid oxidation. These data, together with the existing evidence of glucose hypometabolism in the brains of ε4 carriers, suggest that bioenergetic deficit may be an early event in AD. We therefore hypothesize that APOE ε4 dependent deficits in the transport of peripheral carnitine and acylcarnitines to the brain and in their metabolism in the periphery or in the brain contribute to the brain bioenergetic deficits which make the brain vulnerable to AD pathology. We will first characterize abnormal carnitine and acylcarnitine profiles in the brain and blood of neuropathologically diagnosed AD patients and in AD mouse models to examine the influence of APOE genotypes on the relationship between carnitine/acylcarnitines and AD. We will examine if peripherally administered stable isotope labeled carnitine and acylcarnitines are differentially transported and metabolized in an AD mouse model with 5 x AD mutations and with genetic targeted replacement of murine APOE with human APOE isoforms (EFAD mice). We will also determine whether these changes occur prior to or with the onset of amyloid and tau pathologies. These studies will clarify whether APOE ε4 contributes to both transport and metabolism deficiencies of peripheral carnitine and acylcarnitines and identify new avenues for developing treatment strategies for AD, particularly for ε4 positive individuals who are at a high risk of developing AD.


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 = $0 )
2024	2022	THE ROSKAMP INSTITUTE, INC.	2040 WHITFIELD AVE	SARASOTA	FL	34243	MANATEE	USA	Aging Research	000	2	4/10/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $162,000 )
2022	2022	ROSKAMP INSTITUTE INC, THE	2040 WHITFIELD AVE	SARASOTA	FL	34243	MANATEE	USA	Aging Research	000	2	2/16/2022	NON-COMPETING CONTINUATION	$145,800
2022	2022	ROSKAMP INSTITUTE INC, THE	2040 WHITFIELD AVE	SARASOTA	FL	34243	MANATEE	USA	Aging Research	001	2	6/9/2022	NON-COMPETING CONTINUATION	$16,200
														Subtotal = $162,000

Issue Date FY: 2021 ( Subtotal = $162,000 )
2021	2021	ROSKAMP INSTITUTE INC, THE	2040 WHITFIELD AVE	SARASOTA	FL	34243	MANATEE	USA	Aging Research	000	1	3/11/2021	NEW	$162,000
														Subtotal = $162,000

Grand Total All Awards = $324,000

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The effects of APOE4 on carnitine/acylcarnitine mediated bioenergetic deficits in Alzheimer's disease

Award Number: R03AG070540

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/15/2021

PERIOD OF PERFORMANCE END DATE: 02/29/2024

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