ArticleAge (Dordrecht, Netherlands)2013
Insulin receptor signaling mediates APP processing and β-amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer's disease.
Article in Age (Dordrecht, Netherlands), 2013. 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, 73 citations in OpenAlex.
- Progranulin deficiency in the brain activates an insulin signaling pathway that may promote neurodegeneration.iScience · 2026Article
- Insulin-Like Growth Factor Signaling in Alzheimer's Disease: Pathophysiology and Therapeutic Strategies.Molecular neurobiology · 2025Review
- Role of the Insulin-like Growth Factor System in Neurodegenerative Disease.International journal of molecular sciences · 2024Review
- Strategies for generating mouse model resources of human disease.Protein & cell · 2023Article
- Genetic Reduction of Insulin Signaling Mitigates Amyloid-β Deposition by Promoting Expression of Extracellular Matrix Proteins in the Brain.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
- Sleep deprivation exacerbates microglial reactivity and Aβ deposition in aScience translational medicine · 2023Article
- Neurotrophins and Other Growth Factors in the Pathogenesis of Alzheimer's Disease.Life (Basel, Switzerland) · 2023Review
- Cell non-autonomous regulation of cerebrovascular aging processes by the somatotropic axis.Frontiers in endocrinology · 2023Review
- A Bioinformatics Approach Toward Unravelling the Synaptic Molecular Crosstalk Between Alzheimer's Disease and Diabetes.Journal of Alzheimer's disease : JAD · 2022Article
- Physical Exercise-Induced Myokines in Neurodegenerative Diseases.International journal of molecular sciences · 2021Review
- The Role of Non-coding RNAs in Alzheimer's Disease: From Regulated Mechanism to Therapeutic Targets and Diagnostic Biomarkers.Frontiers in aging neuroscience · 2021Review
- Inflammation and Insulin Resistance as Risk Factors and Potential Therapeutic Targets for Alzheimer's Disease.Frontiers in neuroscience · 2021Review
- Patient hiPSCs Identify Vascular Smooth Muscle Arylacetamide Deacetylase as Protective against Atherosclerosis.Cell stem cell · 2020Article
- Downregulation of Candidate Gene Expression and Neuroprotection by Piperine in Streptozotocin-Induced Hyperglycemia and Memory Impairment in Rats.Frontiers in pharmacology · 2020Article
- Clusterin as a Potential Biomarker of Obesity-Related Alzheimer's Disease Risk.Biomarker insights · 2020Review
- Involvement of insulin receptor substrates in cognitive impairment and Alzheimer's disease.Neural regeneration research · 2019Review
- Consequences of Metabolic Disruption in Alzheimer's Disease Pathology.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2019Review
- Differential effects of diet- and genetically-induced brain insulin resistance on amyloid pathology in a mouse model of Alzheimer's disease.Molecular neurodegeneration · 2019Article
- Role of the Blood-Brain Barrier in Central Nervous System Insulin Resistance.Frontiers in neuroscience · 2019Review
- Insulin Resistance as a Therapeutic Target in the Treatment of Alzheimer's Disease: A State-of-the-Art Review.Frontiers in neuroscience · 2018Review
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In brains from patients with Alzheimer's disease (AD), expression of insulin receptor (IR), insulin-like growth factor-1 receptor (IGF-1R), and insulin receptor substrate proteins is downregulated. A key step in the pathogenesis of AD is the accumulation of amyloid precursor protein (APP) cleavage products, β-amyloid (Aβ)(1-42) and Aβ(1-40). Recently, we and others have shown that central IGF-1 resistance reduces Aβ accumulation as well as Aβ toxicity and promotes survival. To define the role of IR in this context, we crossed neuron-specific IR knockout mice (nIR(-/-)) with Tg2576 mice, a well-established mouse model of an AD-like pathology. Here, we show that neuronal IR deficiency in Tg2576 (nIR(-/-)Tg2576) mice leads to markedly decreased Aβ burden but does not rescue premature mortality of Tg2576 mice. Analyzing APP C-terminal fragments (CTF) revealed decreased α-/β-CTFs in the brains of nIR(-/-)Tg2576 mice suggesting decreased APP processing. Cell based experiments showed that inhibition of the PI3-kinase pathway suppresses endosomal APP cleavage and decreases α- as well as β-secretase activity. Deletion of only one copy of the neuronal IGF-1R partially rescues the premature mortality of Tg2576 mice without altering total amyloid load. Analysis of Tg2576 mice expressing either a dominant negative or constitutively active form of forkhead box-O (FoxO)1 did not reveal any alteration of amyloid burden, APP processing and did not rescue premature mortality in these mice. Thus, our findings identified IR signaling as a potent regulator of Aβ accumulation in vivo. But exclusively decreased IGF-1R expression reduces AD-associated mortality independent of β-amyloid accumulation and FoxO1-mediated transcription.
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Registered trials
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.