ArticleProceedings of the National Academy of Sciences of the United States of America2023
Loss of insulin signaling in astrocytes exacerbates Alzheimer-like phenotypes in a 5xFAD mouse model.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 52 citations in OpenAlex.
- A phase 2A/B randomized trial of metabolic modulators intranasal insulin and empagliflozin for MCI and early AD.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Trial
- "Morphological, Functional, and Molecular Progression of Blood-Brain Barrier Dysfunction in Alzheimer's Disease".Journal of molecular neuroscience : MN · 2026Review
- Establishing a role of the insulin receptor in microglia.Neural regeneration research · 2026Article
- GLP-1 receptor agonists, metabolic syndrome, and Alzheimer's disease: Lessons and opportunities from the EVOKE trials.Journal of neuroendocrinology · 2026Review
- Gut bacterial metabolite imidazole propionate potentiates Alzheimer's disease pathology.Nature communications · 2026Article
- The Interaction Between Insulin Resistance and Neuroinflammation in the Brain and Its Impact on Diabetic Encephalopathy.Biology · 2026Review
- Atypical involvement of Alzheimer's tau proteins in diseases beyond tauopathies.Life medicine · 2026Review
- Intranasal CM-hMSCs modulate brain gene expression linked to glucose metabolism and inflammation in male and female rats exposed to maternal and post-weaning high-fat diets.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Targeting the astrocytic metabolic cascade in Alzheimer's disease: mechanisms, challenges and opportunities.Frontiers in aging neuroscience · 2026Review
- A Novel PROTAC Confers a Dual Benefit Against Amyloid and Tau Pathology in Alzheimer's Disease via DAPK1 Degradation.International journal of biological sciences · 2026Article
- The diabetic retina-brain axis hypothesis in diabetic cognitive impairment: from pathophysiological mechanisms to therapeutic implications.Frontiers in endocrinology · 2026Review
- Expanding the understanding of insulin resistance in brain and periphery.Trends in endocrinology and metabolism: TEM · 2026Review
- The impact of high-sugar diets on central nervous system disorders: mechanisms, pathogenesis, and dietary implication.Annals of medicine · 2025Review
- Death-associated protein kinase 1-dependent SENP1 degradation increases tau SUMOylation and leads to cognitive dysfunction in a mouse model for tauopathy.Molecular neurodegeneration · 2025Article
- The Energetic Collapse of the Alzheimer's Brain: Metabolic Inflexibility Across Cells and Networks.Journal of neurochemistry · 2025Review
- Disease-disease interactions: molecular links of neurodegenerative diseases with cancer, viral infections, and type 2 diabetes.Translational neurodegeneration · 2025Review
- Age-Related Complement C3 Drives Memory Impairments and Associated Neuropathologies in a Mouse Model.Aging cell · 2025Article
- Astrovascular decoupling in awake 5×FAD mice is associated with reduced astrocytic calcium.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Astrocytes of the hippocampus and responses to periprandial neuroendocrine hormones.Physiology & behavior · 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
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
Brain insulin signaling controls peripheral energy metabolism and plays a key role in the regulation of mood and cognition. Epidemiological studies have indicated a strong connection between type 2 diabetes (T2D) and neurodegenerative disorders, especially Alzheimer's disease (AD), linked via dysregulation of insulin signaling, i.e., insulin resistance. While most studies have focused on neurons, here, we aim to understand the role of insulin signaling in astrocytes, a glial cell type highly implicated in AD pathology and AD progression. To this end, we created a mouse model by crossing 5xFAD transgenic mice, a well-recognized AD mouse model that expresses five familial AD mutations, with mice carrying a selective, inducible insulin receptor (IR) knockout in astrocytes (iGIRKO). We show that by age 6 mo, iGIRKO/5xFAD mice exhibited greater alterations in nesting, Y-maze performance, and fear response than those of mice with the 5xFAD transgenes alone. This was associated with increased Tau (T231) phosphorylation, increased Aβ plaque size, and increased association of astrocytes with plaques in the cerebral cortex as assessed using tissue CLARITY of the brain in the iGIRKO/5xFAD mice. Mechanistically, in vitro knockout of IR in primary astrocytes resulted in loss of insulin signaling, reduced ATP production and glycolic capacity, and impaired Aβ uptake both in the basal and insulin-stimulated states. Thus, insulin signaling in astrocytes plays an important role in the control of Aβ uptake, thereby contributing to AD pathology, and highlighting the potential importance of targeting insulin signaling in astrocytes as a site for therapeutics for patients with T2D and AD.
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Registered trials
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