Localization of Lutein in Monkey Brain and its Potential Role in Brain Health.
Abstract: Lutein, a
carotenoid with antioxidant and anti-inflammatory properties, selectively accumulates in
primate brain and may be beneficial for cognition. The combination of lutein with
docosahexaenoic acid (DHA), a long-chain n-3 polyunsaturated fatty acid (PUFA), may
provide additional cognitive benefits. Lutein is known to incorporate into membranes.
However, its distribution in the ... read morebrain, its interactions with nutrients important for
brain health (such as DHA and vitamin E), and its role in brain function remain unclear.
Cognitive impairment is caused by brain cell death, which can result from impaired cell
signaling, oxidative stress, and gene dysregulation. Furthermore, it is known that brain
cell membranes (myelin, neuronal, mitochondrial, and nuclear) are a critical determinant
of cell function and viability. Thus, maintaining structurally healthy and functional
membranes is essential for cognition. The objective of this thesis was to determine the
relationship between lutein and membrane composition and cell viability in regions of
the brain known to control different domains of cognitive function. This objective was
met through two aims using brain tissue from 11 adult rhesus monkeys (age 7-20 y)
obtained from the Oregon National Primate Research Center. Nine monkeys consumed
standard chow (containing 16.4 µmol/kg lutein) while two monkeys consumed the same
chow plus a daily oral lutein supplement (91.16 µmol/g lutein) for 7-12 months
prior to termination. This was done in order to increase the amount of lutein in the
brain, thus, increasing the range of lutein concentrations across brain samples. Lutein
concentrations and fatty acid profiles were determined in isolated nuclear, myelin,
mitochondrial, and neuronal membranes from the striatum, cerebellum, prefrontal cortex,
and hippocampus. The association of lutein and DHA levels within membranes and the
subcellular deposition of vitamin E (α-tocopherol) in relation to lutein were also
evaluated. Secondly, the relationship between region and membrane-specific lutein and
brain cell viability was investigated. Membrane lutein concentrations, which did not
preferentially accumulate in one membrane over another, were not driven by total
membrane PUFA content as is the case with α-tocopherol, an antioxidant found in
significantly higher concentrations in the brain. Membrane lutein accumulation was,
however, related to DHA accumulation within membranes, lending support to the hypothesis
that the two may function together. Lutein was inversely related to DHA in myelin and
neuronal plasma membranes but positively related in mitochondrial membranes, indicating
the nature of this relationship may be membrane-specific. Lutein concentrations were
inversely associated with DHA oxidation more so than arachidonic acid oxidation.
Furthermore, this relationship was observed in mitochondrial membranes only, whereas
total α-tocopherol (not membrane-specific) was related to PUFA oxidation. Nuclear
lutein content was not related to DNA damage, however, nuclear α-tocopherol
concentrations were. Lutein in the neuronal plasma membrane was not related to ERK
activation, while PUFA concentrations in this membrane were positively associated with
activation of this pathway. Although no cause-and-effect conclusions can be drawn from
this thesis, the collective findings suggest that lutein may act as an antioxidant in
the brain but its role may be related to functions other than that of a free radical
scavenger. Results from this thesis provide a critical first step toward understanding
how lutein functions in the brain and have generated hypotheses for future studies
investigating the mechanism underlying the beneficial effect of lutein on
Thesis (Ph.D.)--Tufts University, 2016.
Submitted to the Dept. of Biochemical and Molecular Nutrition.
Advisor: Elizabeth Johnson.
Committee: John Erdman Jr., Oliver Chen, and Nirupa Matthan.
Keywords: Nutrition, Biochemistry, and Health sciences.read less