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Plasma glutamate metabolism correlates with cognitive function and the brain‐adipose axis in a presymptomatic Alzheimer’s cohort
Author(s) -
Fonteh Alfred N.,
Arakaki Xianghong,
Yu Jianquan,
Castor Katherine,
Harrington Michael G.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.038353
Subject(s) - glutamine , medicine , glutamate receptor , endocrinology , lipid metabolism , adipose tissue , cohort , cognitive decline , metabolism , neurotransmitter , chemistry , dementia , biochemistry , disease , central nervous system , amino acid , receptor
Background In addition to the amyloid hypothesis, it is accepted that neurotransmitter and energy dyshomeostasis may underlie AD pathology. Glutamate (Glu) is one of the most common excitatory neurotransmitters and is the precursor of glutamine (Gln) and pyroglutamine (PGln). Glu signaling intersects with lipid metabolism via neuronal phospholipase A 2 activation and the regulation of adiposity. Lipids are a major storage form of energy that is critical to AD pathology. We propose that disturbance in Glu metabolism may interfere with how the brain regulates lipid storage in adipose tissue and its utilization by tissues, and this process can contribute to early AD pathology. Consequently, the aim of our study is to quantify plasma Glu and its metabolites and determine their interaction with lipid metabolism in a pre‐symptomatic AD cohort. Methods We collected fasting blood samples from cognitively healthy (CH) study participants with normal cerebrospinal fluid amyloid/ tau ratio (CH‐NAT, n = 36) or with pathological amyloid/tau ratio (CH‐PAT, n = 34), and from AD participants (n = 26). The concentrations of Glu, Gln, and PGln were measured using liquid chromatography‐tandem mass spectrometry. Blood lipids were measured in a clinical laboratory (HMH, Pasadena) and CSF measures of Aβ 42 and total tau were determined using an ELISA. Results Blood plasma Glu but not Gln and PGln positively correlated with CSF Aβ 42 /T‐tau ratio, in CH and CH‐NAT (p = 0.02) but not in CH‐PAT (p > 0.05) or AD (p = 0.99) participants. Blood plasma Glu also positively correlated with mean diastolic pressure (p = 0.02), BMI (p = 0.001), plasma triglycerides (p < 0.0001), and VLDL‐cholesterol (p < 0.0001), and negatively correlated with HDL‐cholesterol (p = 0.0003), in all CH study participants. Glu did not correlate with BMI but correlated strongly with VLDL‐cholesterol in CH‐NAT. In contrast, Glu correlated with BMI but not with VLDL‐cholesterol in CH‐PAT. Conclusions These data show the differential regulation of blood glutamate metabolism, CSF amyloid/tau, and plasma lipids in pre‐symptomatic AD compared with cognitively healthy participants. We propose that glutamate metabolism and the brain‐adipose interface may be involved in regulating cognitive function and improving its homeostasis may prevent the decline from cognitively healthy to pre‐symptomatic or AD pathology in elderly populations.