Determining the role of lactate metabolism on age‐dependent memory decline and neurodegeneration in Drosophila melanogaster

Abstract

Background Although lactate has traditionally been considered a waste product, recent discoveries show lactate plays many beneficial roles in the brain. Astrocyte generated lactate can function as a fuel for neurons to enable long‐term memory. However, elevated lactate has been detected within the brain and cerebrospinal fluid of Alzheimer’s disease patients; a finding associated with hastened memory impairment. Whether perturbed lactate levels contribute to age‐related memory impairment is unknown. This study uses the fruit fly Drosophila melanogaster to elucidate the role of lactate metabolism in cognition during aging. Method The enzyme lactate dehydrogenase (dLdh), which facilitates the interconversion between lactate and pyruvate, was genetically manipulated in glia and neurons of Drosophila melanogaster. Transgenic flies were tested for changes in lifespan, memory, climbing ability, neurodegeneration as well as dLdh and lactate levels in the brain. Tests in transgenic flies were performed at ages ranging from young (7 days) to old (28 days). Memory was assessed using the courtship conditioning paradigm, of which only male flies can be tested. Results Lactate and dLdh protein levels were correspondingly elevated or lowered in transgenic flies with increased or decreased dLdh expression respectively. Transgenic flies with either increased or decreased dLdh expression exhibited reduction in lifespan and neurodegeneration at old age. These detrimental effects were present whether dLdh expression was altered in either neurons or glia, yet only neuronal dLdh upregulation caused deficits in climbing ability. Young transgenic flies with altered dLdh expression in either neurons or glia all exhibited memory similar to control. Interestingly, only flies with increased glial‐derived dLdh expression had an impact; memory was impaired at middle age then recovered at old age. Conclusion Prolonged perturbation of lactate metabolism results in neurodegeneration and increased rate of health decline in flies. The impact of altered lactate levels on memory appears to be cell type specific and dynamic. Excess glial‐derived lactate only appears detrimental to memory during middle age. However, excess or diminished production of lactate, within neurons or glia, hastens aging and neurodegeneration. Future studies of age‐related diseases, such as Alzheimer’s, should focus on lactate metabolism and metabolic interplay between neurons and glia.

Effects of genetic liability to Alzheimer’s disease on circulating metabolites across the life course

“…The association of AD liability with lactate was positive at older ages in ALSPAC, but inverse or null in UK Biobank age tertiles. Increased lactate in the CSF and brain has been associated with higher AD risk, the degree of perturbation correlating with extent of neurodegeneration 60 . In vitro evidence suggests that this trend may be ε4-mediated 61 , resulting from a 'Warburg like' endophenotype that is present in humans many decades before onset of AD 62 .…”

MED13 and glycolysis are conserved modifiers of α-synuclein-associated neurodegeneration

“…66 However, Ldh overexpression slightly worsened neurodegeneration in fly PR neurons (Figure S5F), consistent with too much and too little Ldh enhancing neurodegeneration and reducing lifespan. 100,101 Therefore, artificially increasing the level of Pgi and Pfk, but not Ldh, is protective.…”

High performance genetically-encoded green fluorescent biosensors for intracellular L-lactate

“…The data were analyzed by FlowJo software (BD). (17,4), and DiLACCO1 = (15,5), where (x, y) = (number of cells in total, number of independent experiments).…”

“…L-Lactate is now known to have many favorable physiological roles as both an energy fuel source 4 and a signaling molecule 5,6 , in processes that include memory consolidation 7 , immune response 8,9 , and neurogenesis 10 . That said, L-lactate is also unfavorably implicated in a number of pathological processes, including inflammation 11,12 , cancer [13][14][15][16] , and neurodegeneration 17 .…”