ArticleProceedings of the National Academy of Sciences of the United States of America2025
Loss of insulin signaling in microglia impairs cellular uptake of Aβ and neuroinflammatory response exacerbating AD-like neuropathology.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed.
- Effect of perioperative intranasal insulin on postoperative delirium in elderly hip fracture patients undergoing general anesthesia: a randomized controlled study.BMC anesthesiology · 2025Trial
- Biliverdin reductase A deficiency reveals sex- and brain region-specific vulnerability to high-fat diet feeding.Redox biology · 2026Article
- Distinct single-nucleus RNA-seq changes among non-neuronal cells in ADNC, LATE-NC, and mixed pathologies.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Brain insulin resistance as a driver of proteinopathy in neurodegeneration: from cell-type-specific mechanisms to targeted therapeutics.Translational neurodegeneration · 2026Review
- GLP-1 receptor agonists, metabolic syndrome, and Alzheimer's disease: Lessons and opportunities from the EVOKE trials.Journal of neuroendocrinology · 2026Review
- Establishing a role of the insulin receptor in microglia.Neural regeneration research · 2026Article
- Reconstituting central nervous system niche cues partially restores homeostatic-like features in cultured murine primary microglia.Scientific reports · 2026Article
- Review
- The insulin receptor inhibitor BMS-754807 alleviates neuroinflammation and Alzheimer's disease pathologies across human cellular and mouse models.Journal of neuroinflammation · 2026Article
- The hypothalamus is an early site of mitochondrial failure and neuro-immune circuit disruption in amyotrophic lateral sclerosis.Molecular metabolism · 2026Article
- Microbiota-Gut-Brain Axis Disruption, Neuroinflammation, and Potential Antioxidant-Based Treatments in Metabolic Diseases.Antioxidants (Basel, Switzerland) · 2026Review
- Acute peripheral versus central inhibition of insulin receptors differentially alters cytokine and blood-brain barrier responses to an inflammatory stimulus.Brain, behavior, and immunity · 2026Article
- Intermittent fasting and neuroprotection in Alzheimer's disease: metabolic mechanisms, cellular signaling, and brain-peripheral crosstalk.Frontiers in nutrition · 2026Review
- Expanding the understanding of insulin resistance in brain and periphery.Trends in endocrinology and metabolism: TEM · 2026Review
- Insulin and IGF signaling in the brain: multilevel regulation of synaptic and network homeostasis.Frontiers in endocrinology · 2026Review
- More than Dysbiosis: Imbalance in Humoral and Neuronal Bidirectional Crosstalk Between Gut and Brain in Alzheimer's Disease.International journal of molecular sciences · 2025Review
- Disease-disease interactions: molecular links of neurodegenerative diseases with cancer, viral infections, and type 2 diabetes.Translational neurodegeneration · 2025Review
- Loss of insulin signaling in microglia impairs cellular uptake of Aβ and neuroinflammatory response exacerbating AD-like neuropathology.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Mechanisms underlying cognitive impairment and management strategies in type 2 diabetes.Frontiers in endocrinology · 2025Review
- Exploring the role of insulin resistance in bridging the metabolic syndrome and Alzheimer's disease-a review of mechanistic studies.Frontiers in endocrinology · 2025Review
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Funding
Abstract
Insulin receptors are present on cells throughout the body, including the brain. Dysregulation of insulin signaling in neurons and astrocytes has been implicated in altered mood, cognition, and the pathogenesis of Alzheimer's disease (AD). To define the role of insulin signaling in microglia, the primary phagocytes in the brain critical for maintenance and damage repair, we created mice with an inducible microglia-specific insulin receptor knockout (MG-IRKO). RiboTag profiling of microglial mRNAs revealed that loss of insulin signaling results in alterations of gene expression in pathways related to innate immunity and cellular metabolism. In vitro, loss of insulin signaling in microglia results in metabolic reprogramming with an increase in glycolysis and impaired uptake of Aβ. In vivo, MG-IRKO mice exhibit alterations in mood and social behavior, and when crossed with the 5xFAD mouse model of AD, the resultant mice exhibit increased levels of Aβ plaque and elevated neuroinflammation. Thus, insulin signaling in microglia plays a key role in microglial cellular metabolism and the ability of the cells to take up Aβ, such that reduced insulin signaling in microglia alters mood and social behavior and accelerates AD pathogenesis. Together, these data indicate key roles of insulin action in microglia and the potential of targeting insulin signaling in microglia in treatment of AD.
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