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) ?4 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 ?4 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 ?4 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 ?4 carriers, reflecting an incomplete fatty acid oxidation. These data, together with the existing evidence of glucose hypometabolism in the brains of ?4 carriers, suggest that bioenergetic deficit may be an early event in AD. We therefore hypothesize that APOE ?4 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 ?4 contributes to both transport and metabolism deficiencies of peripheral carnitine and acylcarnitines and identify new avenues for developing treatment strategies for AD, particularly for ?4 positive individuals who are at a high risk of developing AD.

Public Health Relevance

Late onset Alzheimer?s disease (AD) affects nearly 6 million Americans and the apolipoprotein E (APOE) ?4 allele is the most common genetic risk factor for this condition. To date, AD remains an untreatable condition, and while billions of dollars have been invested on finding disease-modifying drugs that target key hallmarks of AD, such as amyloid, many of these drugs have been unable to substantially reduce cognitive decline in AD patients, suggesting the presence of other biological factors that also contribute to the complex etiology of AD. Therefore, we will target the brain?s energy generation process associated with carnitine/acylcarnitine transport and metabolism as a novel approach in identifying therapies for AD and specifically focus on APOE ?4 positive subjects who are highly susceptible to developing AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Small Research Grants (R03)
Project #
1R03AG070540-01
Application #
10109435
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Dibattista, Amanda
Project Start
2021-03-15
Project End
2023-02-28
Budget Start
2021-03-15
Budget End
2022-02-28
Support Year
1
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Roskamp Institute, Inc.
Department
Type
DUNS #
968547583
City
Sarasota
State
FL
Country
United States
Zip Code
34243