Alzheimer’s disease (AD) is the most common forms of dementia, characterized with loss of memory and cognitive functions. AβPP-PS1 mice exhibit intense plaque load and severe memory loss, which are the hallmark of the AD¹. Neurometabolism has been shown to be reduced in the cerebral cortex and hippocampus in AβPP-PS1 mice². Currently, there is no effective strategy for management/treatment of AD. Dietary restriction (DR) has been shown to increase longevity and neuroprotection on laboratory animals via reduced oxyradical formation and induction of expression of cytoprotective stress proteins³. In the present study, we have evaluated the effects of DR on memory and neurometabolic activity in the AβPP-PS1 mouse model of AD using ¹H-[¹³C]-NMR spectroscopy in conjunction with infusion of [1,6-¹³C₂]glucose.We hypothesized that neuroprotective effects of DR in AβPP-PS1 mice will improve memory and neuronal activity that would result in improved neuronal metabolism.All animal experiments were performed under approved protocols by the Institutional Animal Ethics Committee of CCMB. Male 6 month old mice were divided into following four groups: Group (i) Wild type (WT)+AL (ad libitum)(n=4): WT mice having free access to food and water); (ii) AβPP-PS1+AL: AD mice having free access to food and water (n=5), (iii) WT+DR: WT mice with restricted diet (n=5); (iv) AβPP-PS1+DR: Transgenic mice with restricted diet (n=4). Dietary restriction was carried out starting from six month age by providing food to the animals on alternate day till 12 months. Learning and memory of mice were assessed using Morris Water Maze (MWM) test⁴. For metabolic measurements, urethane (1.5 g/kg, i.p.) anesthetized mice were administered [1,6-¹³C₂]glucose for 10 min through tail vein using bolus variable infusion rate⁵. Blood was collected from sinus orbital and head was frozen in situ with liquid nitrogen at the end of infusion. Metabolites were extracted from frozen cortical and hippocampal tissues. The concentration and ¹³C labeling of brain metabolites were measured in tissue extracts using ¹H-[¹³C]-NMR spectroscopy at 600 MHz NMR spectrometer⁶. Cerebral metabolic rate of glucose oxidation was calculated from the trapping of ¹³C labeled into amino acids neurotransmitters⁷.The latency of AβPP-PS1 mice to reach the hidden platform was found to be significantly (p<0.01) higher than controls in MWM test suggesting impaired memory in AβPP-PS1 mice (Fig. 1). The decreased ¹³C labeling of cortical glutamate-C4, GABA-C2, glutamine-C4 and apartate-C3 (Fig. 2, Table 1) from [1,6-¹³C₂]glucose indicates reduced activity of glutamatergic neurons, GABAergic neurons, and decreased neurotransmission in the cerebral cortex in AβPP-PS1 mice. The cerebral metabolic rates of glucose oxidation by glutamatergic (AβPP-PS1-AL: 0.17±0.03; WT: 0.28±0.05 μmol/g/min, p=0.004) and GABAergic neurons (AβPP-PS1-AL: 0.04±0.01; WT-AL: 0.06±0.01 μmol/g/min, p=0.008) were found to be decreased significantly in AβPP-PS1 mice (Fig. 3). The neurodegenration in AβPP-PS1 mice has been reflected as glucose hypometabolism in cerebral cortex and hippocampus². The latency to reach the hidden platform was found to decreased significantly (p<0.05) in AβPP-PS1 mice subjected to DR (49.8±12.5 s) as compared with those on ad-libitum (82.9±4.2 s) (Fig. 1), suggesting DR himproved memory in AβPP-PS1 mice. Most interestingly, the cortical metabolic rates of glucose oxidation by glutamatergic (0.30±0.02 μmol/g/min) and GABAergic (0.07±0.01 μmol/g/min) neurons were found to be increased to the control levels following six months of DR intervention in AD mice (Fig. 3). Moreover, the impaired neuronal metabolic activity in hippocampus (data not shown) was maintained to control level following DR intervention in AβPP-PS1 mice. It has been established that neurotransmitter cycling flux is stochiometrically coupled to neuronal glucose oxidation⁸. Our finding of increased neuronal glucose oxidation in APP-PS mice with DR suggests an improved excitatory and inhibitory neurotransmission in AD mice. These data suggest that DR intervention at the preclinical stage has potential to manage memory and cognitive function in subjects susceptible for AD.