Monday, July 15, 2013: Poster Presentations: P2 P349
Background: The prodromal phase of Alzheimer’s disease begins decades
prior to clinically detectable dementia; thus, identification of early bio-
markers is critical to identifying at-risk populations. Metabolic changes
in the brain are among the earliest features of the Alzheimer’s pathological
cascade. Estrogen positively regulates the bioenergetic system of the brain
from glucose uptake to ATP generation. Additionally, estrogen regulates
peripheral adipose tissue distribution and promotes healthy fasting insulin
and glucose levels. Consequently, loss of ovarian hormones at menopause
could lead to a state of bioenergetic and metabolic crisis that puts women
at increased risk for AD. Methods:Clinical data and plasma samples were
obtained from women enrolled in the Early vs. Late Intervention Trial
with Estradiol (ELITE). Nine metabolic biomarkers were assessed. Meta-
bolic biomarker clusters were determined using principal components
analysis followed by k-means clustering. Metabolic clusters were stratified
by early or late-menopause, and correlated with cognitive performance.
Results: Preliminary results of metabolic variables measured at 6 months
generated three distinct clusters. Women in Cluster 1 had a healthy meta-
bolic profile; women in Cluster 2 had a metabolic profile indicating risk
of diabetes; and women in Cluster 3 had a pre-hypertensive metabolic pro-
file. Compared to women in Cluster 1, women in Cluster 2 showed signifi-
cantly worse baseline scores on the Trail-Making Test, Part B (p < 0.05).
Preliminary data are consistent with a profile for risk of metabolic and cog-
nitive decline with the menopausal transition. Further analyses are in prog-
ress; baseline and longitudinal cluster data will be presented at the
conference. Conclusions: Outcomes of these analyses will provide meta-
bolic profiles of women at risk for cognitive decline with age and meno-
pause.
P2-011 A BIOENERGETIC TRAJECTORY OF FEMALE
BRAIN AGING AND ALZHEIMER’S DISEASE 1:
IMPLICATIONS FOR RISK PREVENTION AND
TREATMENT
Liqin Zhao1, Jia Yao2, Fan Ding2, Shuhua Chen3, Lauren Klosinski2,
Jamaica Rettberg2, Roberta Brinton2, 1USC School of Pharmacy, Los
Angeles, California, United States; 2University of Southern California, Los
Angeles, California, United States; 3University of Southern California, Los
Angeles, California, United States. Contact e-mail: [email protected]
Background: Both basic science and clinical studies have indicated the
critical role of mitochondrial bioenergetics in brain aging and in the path-
ogenesis of Alzheimer’s disease. Previously, we demonstrated that mito-
chondrial bioenergetic deficits preceded AD pathology in a female triple
transgenic AD (3xTgAD) mouse model. In the present study, we sought
to investigate the temporal trajectory of brain bioenergetic alteration dur-
ing aging and during the development of Alzheimer’s pathology in the
3xTg-AD mouse model. Methods: We conducted a combination of bio-
chemical and functional analyses in female 3xTg-AD and nonTg mice at
age of 3-6-9-12-15 months. Outcomes of investigation included substrate/
fuel supply system, aerobic glycolysis capacity, and mitochondrial catalytic
machinery efficiency. Results: In aging nonTg female mice, alteration in
brain bioenergetics was first evidenced by a decline in brain glucose uptake
between 6 and 9 months, likely attributed to decline in expression of neuro-
nal glucose transporter, compromised hexokinase activity, and inactivation
of pyruvate dehydrogenase complex. In parallel, there was an increase in
plasma level of alternative fuel substrate b-hydroxybutyrate and a concom-
itant increase in its neuronal transporter between 6 and 9months. In contrast,
decline in mitochondrial catalytic capacity, such as decreased mitochondrial
respiration and compromised cytochrome c oxidase activity, reached statis-
tical significance between 9 and 12 months. In 3xTgAD female mice,
3-months-old brains exhibited a bioenergetic profile comparable to
9-months-old nonTg brains. Further, the decrease in glucose utilization
was greatly exacerbated between 6 and 9 months. Moreover, severe deficits
in mitochondrial bioenergetics were accompanied by mitochondrial deposi-
tion of b-amyloid and ABAD between 9 and 12 months. Conclusions: In
female nonTg aging brains, the trajectory of bioenergetic decline started
with compromised substrate availability followed by deficits in mitochon-
drial catalytic capacity. 3xTgAD female brains exhibited early activation
of alternative fuel source, greater deficits in glucose utilization, and mito-
chondrial accumulation of b-amyloid, indicating an accelerated aging phe-
notype in AD brains. The unique trajectory of alterations in brain
bioenergetics during aging and AD development may enable a bioener-
getic-centric strategy that targets disease-stage specific brain metabolism
for prevention and treatment.
P2-012 EARLY DETECTION OFALZHEIMER’S DISEASE:
PROBING MITOCHONDRIAL FUNCTION IN THE
PERIPHERY
Anita Lakatos1, Pinar Coskun1, Jestine Ho2, Ian Smith1, Steven Potkin3,
Andrew Saykin4, Mathew Blurton-Jones5, 1UCI, Irvine, California, United
States; 2Seahorse Bioscience, North Billerica, Massachusetts, United
States; 3University of California Irvine, Irvine, California, United States;4Indiana University, Indianapolis, Indiana, United States; 5University of
California, Irvine, Irvine, California, United States.
Contact e-mail: [email protected]
Background: Human functional (PET) imaging studies have consistently
detected decreased glucose uptake in brain regions associated with learn-
ing and memory in subjects with probable AD and subjects who later
develop AD. Neuronal function, signaling, and connectivity are highly
dependent on glucose utilization coupled with mitochondrial bioener-
getics. Interestingly, mitochondria dysfunction is one of the earliest
indications of pathogenesis in animal models of AD and aging. The
high genetic heritability of AD (59-79%), its strong association with
age, and the emerging non-cognitive peripheral symptoms of the disease
indicate a combined influence of inherited alleles that would likely also
disrupt cellular function in peripheral tissues. Given the considerably over-
lapping transcriptosome between brain cells and lymphoblasts (80%) and
the availability of lymphoblastoid cell lines from patients within the
Alzheimer’s Disease Neuroimaging Study (ADNI), we hypothesized that
lymphoblastoid cells (LCLs) from AD subjects will exhibit impaired
mitochondrial function and other evidence of AD pathogenesis when com-
pared to non-effected controls. Methods: AD and control LCLs cell lines
from the ADNI Consortium were examined. The viability and growth rate
of all cell lines was assessed and b -amyloid (A b) production measured
by ELISA. Lymphoblast mitochondria bioenergetics was also evaluated
with Seahorse XF24 analyzer by measuring oxygen consumption. Mito-
chondrial reactive oxygen species production was assessed with ROS-sensi-
tive dye. Intracellular calcium was measured with a fluorescent indicator
Fura-2AM. Results: Although AD and CTRL LCL viability and growth
rate was equivalent, Ab 40 production was significantly (p�0.031) higher
in AD versus CTRL LCL cells. The mitochondrial bioenergetics also
revealed a significantly lower reserve capacity (p�0.01) in AD LCLs versus
CTRL, and AD cells produced significantly higher amounts of reactive
oxygen species than CTRL LCLs (p� 0.037). Resting cytosolic calcium
(p�0.01) and peak rise in calcium release was also significantly reduced
(p�0.05) in AD versus CTRL LCL cells. Conclusions: Our data demon-
strate that mitochondria function, calcium release, and A b production are
significantly altered in AD-derived lymphoblastoid cells. Taken together,
these data provide initial evidence that energetic and biochemical analysis
of patient-derived lymphoblastoid cells could provide a novel and promising
peripheral approach to diagnose AD or perhaps even predict the develop-
ment of AD.
P2-013 WITHDRAWN
P2-014 PRESENILIN MUTATIONS IMPAIR
MITOCHONDRIAL DYNAMICS IN NEURONS
Xinglong Wang1, Xiongwei Zhu1, George Perry2, Wenzhang Wang3,
Gemma Casadesus1, Hyoung-Gon Lee1, 1Case Western Reserve University,
Cleveland, Ohio, United States; 2University of Texas at San Antonio, San
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