to observe the changes in activities of mitochondrial enzymes (monoamine oxidase (MAO), Na + K + ATPase and Ca 2+ ATPase), membrane fluidity, DNA degradation, and glucose transporter 4 (GLUT3) expression in brains of female Wistar rats of 3 months (young), 12 months (adult) and 24 months (old) age groups, and to see whether these changes are restored to normal levels after exogenous administration of 17b-estradiol (E2) (0.1 mg/gm body weight for one month). Methods: Controls animals received an equal volume of vehicle. After 30 days of hormone treatment, experimental animals of all the groups were sacrificed and brains were isolated for further study. Whole brains were rapidly excised, and washed with chilled normal saline. Tissue homogenates (1:10) were prepared in homogenizing buffer containing 0.25 M sucrose 0.02 M triethanolamine (pH 7.4) and 0.12 mM dithiothreitol. The pellet obtained after centrifugation at 12,000 rpm using SM 22 rotor on a high speed cooling centrifuge (SORVALL 5CA) containing crude synaptosomes (mitochondria and synaptosomes). Results: The results obtained in the present work revealed that normal aging was associated with significant decrease in the activity of Na +- K + ATPase, Ca 2+ ATPase and membrane fluidity, GLUT3 levels in the brains of aging female rats, and an increase in DNA degradation and MAO activity. The present study showed that estradiol treat- ment significantly decreased DNA degradation, and MAO activity in brain of aging rats, and a reversal of Na + K + ATPase, Ca 2+ ATPase and GLUT3 levels was achieved. Conclusions: It can therefore be concluded that estradiol’s beneficial effects seemed to arise from its antilipofuscin, antioxidant, antilipidperoxidative effects, implying an overall anti-aging action. The results of this study will be useful for pharmacological modification of the aging process and applying new strategies for control of age related disorders. O4-03-04 TYPE 3 DIABETES IN ALZHEIMER’S DISEASE: AB-MEDIATED INHIBITION OF EG5/KINESIN 5 LEADS TO INSULIN RECEPTOR AND GLUCOSE TRANSPORTER MIS-LOCALIZATION AND DYSFUNCTION Athena Wang 1 , Esteban Lucero 1 , Steven Bennett 1 , Huntington Potter 2,3 , 1 University of Colorado Anschutz Medical Campus, Aurora, CO, USA; 2 Linda Crnic Institute for Down Syndrome, Aurora, CO, USA; 3 University of Colorado Anschutz Medical Campus, Denver, CO, USA. Contact e-mail: athena.wang@ucdenver.edu Background: Is Alzheimer disease (AD) a Type 3 diabetes? Previ- ous FDG-PET studies showed that subjects with mild cognitive impairment (MCI) or early AD exhibited reduced glucose utiliza- tion and potentially insulin resistance in the brain. A preliminary clinical trial of intranasal insulin therapy showed improved cogni- tive function in patients with amnestic MCI or AD (Craft et al., 2012). These and other findings provide evidence that glucose uti- lization and/or insulin receptor function may be disrupted in AD. However, the mechanism(s) underlying this defect remain unclear. Previous studies from our laboratory have shown that the microtubule-related motor protein Eg5/Kinesin 5 is inhibited by Ab42 oligomers, resulting in chromosome mis-segregation and neurotransmitter and neurotrophin receptor mislocalization and dysfunction (Ari et al., 2010). Such disruption of microtubule- based transport may explain the previous finding of the mis-local- ization of some, but not all, membrane proteins, such as the insulin receptor (Zhao et al., 2008). Methods: In this study, we used immu- nohistochemistry to examine the effects of treatment with Ab42 (2 mM) or with the Eg5 inhibitor monastrol (10 mM) on the distribution of insulin receptors and glucose transporters in cultured cells and the localization of the receptors in hippocampus and cortex in a rat model of AD. Results: The results show that glucose transporter distribution in primary rat astrocytes is disrupted by Ab42 oligo- mers and by monastrol, resulting in aggregated/clustered glucose transporters in a peri-nuclear region. Insulin receptors also ap- peared to be clustered in a peri-nuclear region following treatment with Ab42 (2 mM) or monastrol (10 mM) for 48 h in cultured N2A or PC12 cells. We observed the same results in rat primary cortical neurons. We also found that disruption of insulin receptor distribution could be rescued by Eg5 overexpression in N2A cells. Furthermore, in a rat model of AD, the insulin receptor was abnor- mally clustered in peri-nuclear regions in the hippocampus and cor- tex. Conclusions: These findings provide evidence that Ab42- induced dysregulation of the microtubule network disrupts insulin receptor and glucose transporter trafficking, which is likely to nega- tively impact neuronal energy metabolism and synaptic plasticity, and suggest that Ab-mediated inhibition of Eg5/Kinesin 5 may be an important AD therapeutic target. O4-03-05 TOR AS A KEY REGULATOR OF NEURONAL AND BRAIN VASCULAR FUNCTION IN MOUSE MODELS OF ALZHEIMER’S DISEASE Veronica Galvan 1 , Stacy Hussong 1 , Jonathan Halloran 2 , Raquel Burbank 3 , Kathleen Fischer 4 , Steven Austad 4 , Ai-Ling Lin 5 , James Cuvillier 1 , Candice Van Skike 1 , Carlos Pomilio 6 , 1 University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; 2 University of California, Berkeley, Berkeley, CA, USA; 3 University of New Mexico, Albuquerque, Albuquerque, NM, USA; 4 University of Alabama, Birmingham, Birmingham, AL, USA; 5 University of Kentucky, Lexington, KY, USA; 6 University of Buenos Aires, Buenos Aires, Argentina. Contact e-mail: galvanv@uthscsa.edu Background: We recently showed that chronic treatment with the target-of-rapamycin (TOR) inhibitor rapamycin, a drug that extends lifespan and delays aging in mice, halted and even reversed Alz- heimer’s (AD)-like memory deficits, decreased Ab, and restored ce- rebral blood flow (CBF) in brains of hAPP(J20) and Tg2576 mice modeling the disease. Reducing TOR activity also restored cogni- tive function and CBF in mice modeling atherosclerosis, as well as in 36 month-old rats. Attenuating TOR activity was associated with the recovery of cortical network activation and functional hy- peremia evoked by somatosensory stimulation. Our data indicate that the mechanisms by which TOR attenuation restores CBF, neuronal activity, and cognitive function may be common to different models of age-associated neurological disease and to brain aging, and singled out (a) vascular NO release, and (b) synaptic bou- ton remodeling as key mechanisms by which TOR attenuation blocks AD-like progression in mice. Methods: To delineate the mech- anisms by which TOR regulates synaptic remodeling during aging and in AD we used rapamycin in very old rats, and advanced tissue-specific genetic tools to reduce TOR complex 1 assembly specifically in neurons of adult mice. Results: Moderate, but not drastic reduction of TORC1 assembly in neurons, to levels similar to those achieved by rapamycin treatment, promoted synaptic remodeling and increased autophagy, potentially increasing synaptic vesicle recycling. This was associated with enhanced memory and increased brain glucose uptake, suggestive of increased brain glucose metabolism. We propose that attenuation of TOR in (a) brain vascular endothelial cells and in (b) Ab-producing parenchymal neurons by pharmacological or genetic means act syner- gistically to slow the progression of AD dysfunction through the resto- ration of (1) NO-dependent vasodilation and CBF, increasing vascular Ab clearance, and (2) by increasing autophagy at synapses, leading to Podium Presentations: Wednesday, July 27, 2016 P338