ArticleSignal transduction and targeted therapy2024
A positive feedback inhibition of isocitrate dehydrogenase 3β on paired-box gene 6 promotes Alzheimer-like pathology.
Article in Signal transduction and targeted therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 41 papers, 1 of them a synthesis that pooled it.
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Who cites it
41 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Lactylation and its roles in diseases: a systematic bibliometric exploration of the research landscape.Frontiers in oncology · 2025Pooled it
- Histone H4 lysine 12 lactylation-driven ZIP14 expression is involved in electroacupuncture therapy against cerebral ischemia/reperfusion injury in mice.Journal of advanced research · 2026Article
- Lysine l-Lactylation: Bridging Metabolism, Chromatin and Disease.Cell proliferation · 2026Review
- Novel protein acylations in Alzheimer's disease: Molecular, mechanisms, biological significance, and diagnostic and therapeutic potentials.Journal of advanced research · 2026Review
- PIAS1-mediated GSK3β SUMOylation exacerbates tauopathy and cognitive deficits in Alzheimer's disease models.Molecular psychiatry · 2026Article
- Protein lactylation in health and diseases: molecular mechanisms, biological significance, and clinical implications.Signal transduction and targeted therapy · 2026Review
- Single-cell multi-omics sequencing reveals cell-specific transcriptomic and chromatin accessibility profiles in gut microbiome metabolite butyrate-produced pain modulation.International journal of oral science · 2026Article
- From Lipids to Mitochondria: Shared Metabolic Alterations in Obesity and Alzheimer's Disease.Cells · 2026Review
- Lactylation formation, gene regulation, biological functions, and clinical relevance.Histology and histopathology · 2026Review
- Article
- Glycolysis enzymes and cellular lactylation in tumour.Clinical and translational medicine · 2026Review
- From metabolic substrate to epigenetic regulation: roles and mechanisms of lactylation in brain health and disease.Frontiers in molecular neuroscience · 2026Review
- Histone lactylation-mediated glycolysis-ferroptosis axis in neurological diseases.Frontiers in molecular neuroscience · 2026Review
- Protein lactylation in Alzheimer's disease: bridging metabolism, pathology, and therapeutic opportunity.Frontiers in aging neuroscience · 2026Review
- Dual roles of lactate and lactylation modification in the nervous system: neuroprotection and neuroinjury.Frontiers in aging neuroscience · 2026Review
- When metabolic enzymes meet lactylation: a bidirectional dialogue in health and disease.Frontiers in cell and developmental biology · 2026Review
- Beyond Fuel: Exercise-Induced Lactate as a Metabolic-Epigenetic Regulator in Central Nervous System Health and Disease.Biomolecules · 2025Review
- Genetic Evidence Linking Lactylation-Related Gene Expression To Dementia Risk.Neuromolecular medicine · 2025Article
- Gut Acetic Acid Alleviates Cognitive Impairment by Inhibiting Tau Hyperphosphorylation via Regulating FFAR3/Erk Pathway in Chronic Cerebral Ischemia Mice.Molecular neurobiology · 2025Article
- Aerobic Exercise Attenuates Autophagy-Lysosomal Flux Deficits via β2-AR-Mediated ESCRT-III Subunit CHMP4B in Mice With Human MAPT P301L.Aging cell · 2025Article
Corrections and comments
- Erratum issued
Authors and funding
10 authors.
Funding
Abstract
Impaired brain glucose metabolism is an early indicator of Alzheimer's disease (AD); however, the fundamental mechanism is unknown. In this study, we found a substantial decline in isocitrate dehydrogenase 3β (IDH3β) levels, a critical tricarboxylic acid cycle enzyme, in AD patients and AD-transgenic mice's brains. Further investigations demonstrated that the knockdown of IDH3β induced oxidation-phosphorylation uncoupling, leading to reduced energy metabolism and lactate accumulation. The resulting increased lactate, a source of lactyl, was found to promote histone lactylation, thereby enhancing the expression of paired-box gene 6 (PAX6). As an inhibitory transcription factor of IDH3β, the elevated PAX6 in turn inhibited the expression of IDH3β, leading to tau hyperphosphorylation, synapse impairment, and learning and memory deficits resembling those seen in AD. In AD-transgenic mice, upregulating IDH3β and downregulating PAX6 were found to improve cognitive functioning and reverse AD-like pathologies. Collectively, our data suggest that impaired oxidative phosphorylation accelerates AD progression via a positive feedback inhibition loop of IDH3β-lactate-PAX6-IDH3β. Breaking this loop by upregulating IDH3β or downregulating PAX6 attenuates AD neurodegeneration and cognitive impairments.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.