Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common cause of dementia in elderly population. The epidemiological study has indicated a steep rise in the prevalence of AD beyond the age of 70 years. The dementing condition has been reported to be more prevalent in men than female until the age of 89 year and trend become inverse after it¹. The epidemiological studies have suggested that contribution of women to AD is more than men beyond the age of 90 years. However, a recent study has suggested the proportion of persons suffering with AD is always higher in women than in men². It is not clear whether the high prevalence of AD in female is due to higher risk of disease in women or solely due to more longevity of women³. In the present study, we explored the neurotransmitter metabolism in APP-PS1 female mice and compared with age matched male mice to understand the impact of gender in the severity of AD in transgenic model of the disease.All animal experiments were performed under approved protocols by the Institutional Animal Ethics Committee of CCMB. Following four groups of 12 month age mice were studied: Group (i) APP-PS1 male (AD-M; n=6), (ii) Wild Type Male (WT-M; n=5), (iii) APP-PS1 female (AD-F; n=6) (iv) Wild type female (WT-F; n=5). Mice were maintained at temperature ~22°C, relative humidity 55-65% and 12h/12h light/dark cycle. Memory of mice were assessed using Morris Water Maze (MWM) test⁴. Cerebral metabolism was studied in overnight fasted mice under urethane (1.5 g/kg, i.p.) anesthesia. The lateral tail vein was cannulated for infusion of ¹³C labeled glucose. Core body temperature was maintained at ~37°C. [1,6-¹³C₂]Glucose was administered in mice using a bolus-variable rate infusion protocol⁵. Blood was collected from orbital sinus just before the end of the infusion, and brain was frozen in situ in liquid nitrogen. Metabolites were extracted from frozen cortical tissue, hippocampal and striatal tissue⁶. The concentration and ¹³C labeling of metabolites were measured in tissue extracts using ¹H-[¹³C]-NMR spectroscopy at 600 MHz NMR spectrometer⁷. Cerebral metabolic rate of glucose oxidation was calculated from the trapping of ¹³C labeled into amino acids neurotransmitters⁸.The male AD mice took significantly (p<0.01) longer time to reach the hidden platform than wild type controls (Fig. 1). Further, the latency for female AD mice was also significantly (p<0.01) higher time than WT control, suggesting impairment in female AD mice. A typical ¹H-[¹³C]-NMR spectrum recorded from the cortical tissue extract is presented in Fig. 2. The concentration of ¹³C labeled glutamate-C4, GABA-C2 glutamine-C4 and asparate-C3 from [1,6-¹³C₂]glucose in the cerebral cortex was found to be significantly lower (P<0.05) in male APP-PS1 mice as compared with male controls (Table 1). Similar results were seen in hippocampal and cortical regions. Interestingly, no significant difference was observed for the ¹³C labeling of amino acids in the cerebral cortex (p≥0.12) and hippocampus (p≥0.17) in female transgenic mice when compared with WT controls. The male transgenic mice exhibit significant reduction in the cerebral metabolic rates of glucose oxidation by glutamatergic (AD-M: 0.16±0.01; WT-M: 0.21±0.05 μmol/g/min, p=0.004) and GABAergic neurons (APP-M: 0.04±0.01; WT-M: 0.05±0.01 μmol/g/min, p=0.019) in cerebral cortex as compared with WT males (Fig. 3). Reduction in the cerebral metabolic rates of glucose oxidation for glutamatergic and GABAergic neurons were also observed in the hippocampus and striatum of the transgenic male mice (data not shown). In contrary, transgenic female mice did not show change in metabolic rates of glucose oxidation in the cerebral cortex (APP-F: 0.29±0.02; WT-F: 0.32±0.05 μmol/g/min, p=0.16), hippocampus (APP-F: 0.27±0.02; WT-F 0.27±0.06 μmol/g/min, p=0.39), and striatum (APP-F: 0.25±0.02; WT-F 0.27±0.03 μmol/g/min, p=0.07) as compared with the respective wild-type controls (Fig. 4). Estrogen, a female harmone, has been shown to regulate the level of enzymes superoxide dismutase and glutathione peroxidase, and protects mitochondria from the reactive oxygen species: thus increases longevity in females⁹. Moreover, it has been suggested that estrogens protect against neuronal toxicity of Aβ peptide¹⁰. Our finding of no change in neurometabolic activity in female AβPP-PS1 mice at the age of 12 months is in good accordance with a hypothesis suggesting estrogen protects brain against Aβ neurotoxicity. Further studies are needed at higher age are needed to dissect the role of estrogens for suppression of AD in females.