Aberrant energy metabolism in Alzheimer’s disease

Abstract

To maintain energy supply to the brain, a direct energy source called adenosine triphosphate (ATP) is produced by oxidative phosphorylation and aerobic glycolysis of glucose in the mitochondria and cytoplasm. Brain glucose metabolism is reduced in many neurodegenerative diseases, including Alzheimer’s disease (AD), where it appears presymptomatically in a progressive and region-specific manner. Following dysregulation of energy metabolism in AD, many cellular repair/regenerative processes are activated to conserve the energy required for cell viability. Glucose metabolism plays an important role in the pathology of AD and is closely associated with the tricarboxylic acid cycle, type 2 diabetes mellitus, and insulin resistance. The glucose intake in neurons is from endothelial cells, astrocytes, and microglia. Damage to neurocentric glucose also damages the energy transport systems in AD. Gut microbiota is necessary to modulate bidirectional communication between the gastrointestinal tract and brain. Gut microbiota may influence the process of AD by regulating the immune system and maintaining the integrity of the intestinal barrier. Furthermore, some therapeutic strategies have shown promising therapeutic effects in the treatment of AD at different stages, including the use of antidiabetic drugs, rescuing mitochondrial dysfunction, and epigenetic and dietary intervention. This review discusses the underlying mechanisms of alterations in energy metabolism in AD and provides potential therapeutic strategies in the treatment of AD.

Characterizing Molecular and Synaptic Signatures in mouse models of Late-Onset Alzheimer’s Disease Independent of Amyloid and Tau Pathology

“…By contrast, LOAD2+HFD mice at 18 mos, resulted in whole brain increases in perfusion and metabolism. Importantly, these changes were observed in both sexes, and was consistent with reports of prodromal hyper-metabolism 36-39 and hyperemia 40 observed in clinical patients, suggesting that this model recapitulates the earliest manifestations of LOAD.…”

Association of genetically predicted 486 blood metabolites on the risk of Alzheimer’s disease: a Mendelian randomization study

“…Blood metabolites, with the noninvasive detection, amenability to intervention, and the capability of many to traverse the blood-brain barrier, are regarded as valuable markers to fulfill this goal (Enche et al, 2017;Lord et al, 2021). An increasing amount of evidence indicates that abnormalities in blood metabolism could be related to the degree of neuropathology of AD and affected the eventual manifestation of symptoms (Varma et al, 2018;Kuehn, 2020;Peng et al, 2020;Yu et al, 2022). Nevertheless, the uncertain link between these abnormalities and AD limits their utility in early detection.…”

Cardiovascular risk burden, dementia risk and brain structural imaging markers: a study from UK Biobank

“… 27 The most common and plausible mechanisms that link atrial fibrillation, ischaemic heart disease and heart failure to dementia may involve cerebral hypoperfusion and hypoxia, cerebral ischaemia or microbleeds, and the release of natriuretic peptides. 28 The unexplained dementia risk of the cardiovascular burden caused by major CVD events may involve other mechanisms, including cerebral small vessel lesions and microinfarctions not reaching the stage of clinically diagnosed CVD, oxidative stress, inflammation and aberrant brain energy metabolism, 29 which warrant confirmation by further studies.…”