Acta Neuropathol (2011) 122:293–311 299 Fig. 2 Blood-to-brain glucose uptake and astrocytic lactate release upon neuronal stimulation are impaired in TG arcAb mouse brain starting at mid-stage pathology. a Lower baseline glucose concentra- tion proﬁle in hippocampal ECF microdialysate of mid-stage TG arcAb mice as compared to their NTG littermates. Microdialysis samples were taken in 30-min intervals over 10 h. On average baseline hippocampal glucose was about 30% lower in TG animals as compared to their NTG littermates. Note the higher degree of intra- individual deviation in the TG animals, possibly due to the heterogeneity of CAA and/or Ab plaque load in this group. b No differences were found in plasma glucose levels between TG arcAb mice and their NTG littermates. Blood was withdrawn from the tail vein of the mice after an 8-h period of fasting. Mean plasma glucose concentration for both TG and NTG animals was around 3.5 mmol/l. c Graph illustrating impaired rise in glucose in hippocampal ECF of TG arcAb mice upon systemic administration of glucose alone (sample 5, single arrow) and in combination with neuronal stimula- tion using potassium chloride (KCl) (sample 24, double arrows). Intraperitoneal injection of 250 mM D-glucose in TG arcAb mice and is derived from glucose and released by astrocytes upon uptake of neuronal-secreted glutamate in the synaptic cleft during neuronal stimulation [32, 37, 38]. Lactate was measured in the same microdialysate samples as collected for glucose uptake analyses (Fig. 2d). As can be seen from Fig. 2d, baseline lactate levels were not different between TG animals and their NTG littermates and not affected by intraperitoneal administration of glucose (sample 5, single arrow). However, retrodialysis of 120 mM KCl led to a fast and steep increase in lactate levels in the microdialysate of NTG animals, a response which was less pronounced (sample 24, double arrows) and more protracted in the TG mice (samples 24–27). their NTG littermates (sample 5, single arrow) after 12 h of fasting led to a sharp increase in hippocampal ECF glucose in NTG animals, whereas the TG animals did not demonstrate such rise in glucose levels. However, intraperitoneal injection of 250 mM D-glucose in combination with neuronal stimulation by retrodialysis of 120 mM KCl (sample 24, double arrows) into the hippocampal ECF both TG and NTG animals showed an increase in glucose. d Impaired increase in lactate concentrations in TG animals upon neuronal stimulation. No difference in basal lactate levels was found between TG animals and their NTG littermates (samples 1–23). Lactate was measured in the same microdialysate samples as collected for glucose uptake analyses (Fig. 2a). Note that intraperitoneal administration of glucose did not have an effect on lactate concentrations (sample 5, single arrow). Retrodialysis of 120 mM KCl (sample 24, double arrows) led to a fast and steep increase in lactate levels in the microdialysate of NTG animals, a response which was not found in the TG mice. The TG animals showed slower and smaller rise in lactate and a delay in the time to reach baseline concentrations This ﬁnding prompted us to further study the possibility of a deﬁciency in lactate release by arcAb astrocytes. To this aim, the expression of the astrocytic lactate trans- porter monocarboxylate transporter 1 (MCT1)—which transports lactate from the astrocyte cytoplasm into the ECF where it can be taken up by neurons—was assessed as well as the concentration of lactate released in culture medium of ex vivo-cultured astrocytes derived from the same cohort of mid-stage arcAb mice. A strongly reduced expression of the lactate transporter was found in the astrocyte lysates as demonstrated by WB (Fig. 3a) as was a signiﬁcantly decreased lactate release ex vivo (Fig. 3b). 123