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: liqinz@usc.edu

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: alakatos@uci.edu

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