ArticleAging cell2019
Age-associated cholesterol reduction triggers brain insulin resistance by facilitating ligand-independent receptor activation and pathway desensitization.
Article in Aging cell, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 42 citations in OpenAlex.
- Lipidomic profiling reveals age-dependent changes in plasma membrane lipids that affect neural stem cell aging.Science advances · 2026Article
- The role of lipid metabolism in neuronal senescence.FEBS open bio · 2026Review
- Review
- Streptozotocin and L-Buthionine-Sulfoximine Decrease Neuron Membrane Lipid Packing and Alter Insulin Signaling.Neurotoxicity research · 2025Article
- Current View on PPAR-α and Its Relation to Neurosteroids in Alzheimer's Disease and Other Neuropsychiatric Disorders: Promising Targets in a Therapeutic Strategy.International journal of molecular sciences · 2024Review
- Oxysterols in Central and Peripheral Synaptic Communication.Advances in experimental medicine and biology · 2024Article
- Mutant APC reshapes Wnt signaling plasma membrane nanodomains by altering cholesterol levels via oncogenic β-catenin.Nature communications · 2023Article
- Diversity of Structural, Dynamic, and Environmental Effects Explain a Distinctive Functional Role of Transmembrane Domains in the Insulin Receptor Subfamily.International journal of molecular sciences · 2023Article
- Alzheimer's disease: an axonal injury disease?Frontiers in aging neuroscience · 2023Review
- Insulin-like growth factor I sensitization rejuvenates sleep patterns in old mice.GeroScience · 2022Article
- Brain Mitochondrial Dysfunction: A Possible Mechanism Links Early Life Anxiety to Alzheimer's Disease in Later Life.Aging and disease · 2022Article
- Cholesterol determines the cytosolic entry and seeded aggregation of tau.Cell reports · 2022Article
- Diet-responsive transcriptional regulation of insulin in a single neuron controls systemic metabolism.PLoS biology · 2022Article
- Hypothalamic pregnenolone mediates recognition memory in the context of metabolic disorders.Cell metabolism · 2022Article
- Plasma membrane and brain dysfunction of the old: Do we age from our membranes?Frontiers in cell and developmental biology · 2022Review
- The mechanism and efficacy of GLP-1 receptor agonists in the treatment of Alzheimer's disease.Frontiers in endocrinology · 2022Review
- Increased exosome secretion in neurons aging in vitro by NPC1-mediated endosomal cholesterol buildup.Life science alliance · 2021Article
- Sleep Disturbances and Cognitive Impairment in the Course of Type 2 Diabetes-A Possible Link.Current neuropharmacology · 2021Article
- Amelioration of Hippocampal Insulin Resistance Reduces Tau Hyperphosphorylation and Cognitive Decline Induced by Isoflurane in Mice.Frontiers in aging neuroscience · 2021Article
- Lovastatin Differentially Regulates α7 and α4 Neuronal Nicotinic Acetylcholine Receptor Levels in Rat Hippocampal Neurons.Molecules (Basel, Switzerland) · 2020Article
Corrections and comments
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Authors and funding
9 authors at 5 institutions in 5 countries.
Funding
Abstract
In the brain, insulin plays an important role in cognitive processes. During aging, these faculties decline, as does insulin signaling. The mechanism behind this last phenomenon is unclear. In recent studies, we reported that the mild and gradual loss of cholesterol in the synaptic fraction of hippocampal neurons during aging leads to a decrease in synaptic plasticity evoked by glutamate receptor activation and also by receptor tyrosine kinase (RTK) signaling. As insulin and insulin growth factor activity are dependent on tyrosine kinase receptors, we investigated whether the constitutive loss of brain cholesterol is also involved in the decay of insulin function with age. Using long-term depression (LTD) induced by application of insulin to hippocampal slices as a read-out, we found that the decline in insulin function during aging could be monitored as a progressive impairment of insulin-LTD. The application of a cholesterol inclusion complex, which donates cholesterol to the membrane and increases membrane cholesterol levels, rescued the insulin signaling deficit and insulin-LTD. In contrast, extraction of cholesterol from hippocampal neurons of adult mice produced the opposite effect. Furthermore, in vivo inhibition of Cyp46A1, an enzyme involved in brain cholesterol loss with age, improved insulin signaling. Fluorescence resonance energy transfer (FRET) experiments pointed to a change in receptor conformation by reduced membrane cholesterol, favoring ligand-independent autophosphorylation. Together, these results indicate that changes in membrane fluidity of brain cells during aging play a key role in the decay of synaptic plasticity and cognition that occurs at this late stage of life.
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