Aerobic Glycolysis in the Frontal Cortex Correlates with Memory Performance in Wild-Type Mice But Not the APP/PS1 Mouse Model of Cerebral Amyloidosis

Abstract

Aerobic glycolysis and lactate production in the brain plays a key role in memory, yet the role of this metabolism in the cognitive decline associated with Alzheimer's disease (AD) remains poorly understood. Here we examined the relationship between cerebral lactate levels and memory performance in an APP/PS1 mouse model of AD, which progressively accumulates amyloid-␤. In vivo 1 H-magnetic resonance spectroscopy revealed an age-dependent decline in lactate levels within the frontal cortex of control mice, whereas lactate levels remained unaltered in APP/PS1 mice from 3 to 12 months of age. Analysis of hippocampal interstitial fluid by in vivo microdialysis revealed a significant elevation in lactate levels in APP/PS1 mice relative to control mice at 12 months of age. An age-dependent decline in the levels of key aerobic glycolysis enzymes and a concomitant increase in lactate transporter expression was detected in control mice. Increased expression of lactate-producing enzymes correlated with improved memory in control mice. Interestingly, in APP/PS1 mice the opposite effect was detected. In these mice, increased expression of lactate producing enzymes correlated with poorer memory performance. Immunofluorescent staining revealed localization of the aerobic glycolysis enzymes pyruvate dehydrogenase kinase and lactate dehydrogenase A within cortical and hippocampal neurons in control mice, as well as within astrocytes surrounding amyloid plaques in APP/PS1 mice. These observations collectively indicate that production of lactate, via aerobic glycolysis, is beneficial for memory function during normal aging. However, elevated lactate levels in APP/PS1 mice indicate perturbed lactate processing, a factor that may contribute to cognitive decline in AD.

Magnetic resonance spectroscopy reveals abnormalities of glucose metabolism in the Alzheimer's brain

“…This corroborates the recent finding of elevated MRS‐measured lactate in transgenic AD mice compared to wild‐type mice, in which it is associated with memory deficits 56. Whereas older MRS studies failed to show any discernable lactate differences in AD,57, 58 our finding and that of a recent study54 align with this very strong mechanistic data 55, 56. Despite the biological plausibility of the finding, we interpret our results on Lac with caution as quantitation of Lac can be affected by signals from macromolecules which partially overlap with the Lac signal in the J‐PRESS spectrum 24…”

“…In this study, we found an elevation in lactate in AD compared to control subjects, which also survived the correction made for CSF volume. This corroborates the recent finding of elevated MRS‐measured lactate in transgenic AD mice compared to wild‐type mice, in which it is associated with memory deficits 56. Whereas older MRS studies failed to show any discernable lactate differences in AD,57, 58 our finding and that of a recent study54 align with this very strong mechanistic data 55, 56.…”

“…56 Whereas older MRS studies failed to show any discernable lactate differences in AD, 57,58 our finding and that of a recent study 54 align with this very strong mechanistic data. 55,56 Despite the biological plausibility of the finding, we interpret our results on Lac with caution as quantitation of Lac can be affected by signals from macromolecules which partially overlap with the Lac signal in the J-PRESS spectrum. 24 We also found Asc levels were higher in AD subjects, which is an interesting finding as this metabolite's role in brain function is still not clearly understood.…”

The Effects of Peripheral and Central High Insulin on Brain Insulin Signaling and Amyloid-β in Young and Old APP/PS1 Mice

“…We previously saw an exaggerated response in ISF A␤ to hyperglycemia in aged mice with significant amyloid pathology (Macauley et al, 2015). Here, we report new found differences at baseline in blood and ISF glucose between young and aged APP/PS1 mice that correspond with changes in lactate that we previously reported (Harris et al, 2016). Conversely, there was no baseline difference in blood insulin levels, which may explain why we saw an exaggerated response to hyperglycemia in aged mice but a similar response to insulin.…”

“…4 A, B). Previously, we reported that baseline hippocampal ISF lactate levels were significantly increased in 12-month-old APP/PS1 mice compared with 3-monthold APP/PS1 mice (Harris et al, 2016). Here, we found that fasted blood glucose as well as hippocampal ISF glucose were lower in 12-month-old compared with 3-month-old APP/PS1 mice (blood: p Ͻ 0.001, t ϭ 4.1, 129.0 Ϯ 5 vs 95.9 Ϯ 6.5 mg/dl; ISF: p Ͻ 0.01, t ϭ 2.5, 0.20 Ϯ 0.01 vs 0.15 Ϯ 0.01 mM) (Fig.…”