Authors
Yewon Chang, Hee-Joo Kim, Yeongmin Kim, Aron Park, Seungyoon Nam, Deveena R Banerjee, Clinton M Hasenour, Jamey D Young, George A Brooks, Robert R Wolfe, Il-Young Kim
Published in
American journal of physiology. Cell physiology. Aug 21, 2026. Epub Aug 21, 2026.
Abstract
A growing body of evidence has demonstrated the existence of metabolic dysfunction in neurodegenerative diseases, including Alzheimer's disease (AD), suggesting that deprivation of energy substrates impairs cellular dynamics. As the glucose utilization declines in AD patients, the need for alternative energy sources becomes crucial to sustain neuronal activities and prevent cell death induced by neurotoxic proteins, such as amyloid beta (A) aggregates. In this context, lactate has been investigated as a potential alternative brain energy substrate in several studies, yet its impact on neuronal cells under A-induced toxicity remains unclear. We confirmed significant suppression of energy production-related biological pathways by analyzing brain transcriptomic data of AD patients. In subsequent in vitro studies, exogenous lactate treatment ameliorated neuron-like cell death caused by A aggregates. Using a 13C stable isotope tracer, we verified cellular lactate uptake and its incorporation into TCA cycle in neurons under the neurotoxic condition. ¹³C metabolic flux analysis further supported these findings by revealing that lactate treatment restored Aβ-suppressed mitochondrial TCA cycle fluxes. These metabolic improvements were accompanied by increased expression of mitochondrial proteins. These findings support lactate shuttling as a mechanism for supplying lactate-derived carbon to mitochondrial energy metabolism, which may improve neuronal resilience under Aβ-induced metabolic stress.
PMID:
42627738
Bibliographic data and abstract were imported from PubMed on 22 Aug 2026.
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