Related Experiment Videos
Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation
Markus Schubert1, Derek P Brazil, Deborah J Burks
1Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Abstract:
Insulin resistance and diabetes might promote neurodegenerative disease, but a molecular link between these disorders is unknown. Many factors are responsible for brain growth, patterning, and survival, including the insulin-insulin-like growth factor (IGF)-signaling cascades that are mediated by tyrosine phosphorylation of insulin receptor substrate (IRS) proteins. Irs2 signaling mediates peripheral insulin action and pancreatic beta-cell function, and its failure causes diabetes in mice. In this study, we reveal two important roles for Irs2 signaling in the mouse brain. First, disruption of the Irs2 gene reduced neuronal proliferation during development by 50%, which dissociated brain growth from Irs1-dependent body growth. Second, neurofibrillary tangles containing phosphorylated tau accumulated in the hippocampus of old Irs2 knock-out mice, suggesting that Irs2 signaling is neuroprotective. Thus, dysregulation of the Irs2 branch of the insulin-Igf-signaling cascade reveals a molecular link between diabetes and neurodegenerative disease.
Insights
Insulin receptor substrate 2 (Irs2) signaling is crucial for brain development and neuroprotection. Its disruption links diabetes to neurodegenerative diseases like Alzheimer's by impairing neuronal growth and promoting tau pathology.
Area of Science:
- Neuroscience
- Endocrinology
- Molecular Biology
Background:
- Insulin resistance and diabetes are potential risk factors for neurodegenerative diseases.
- The insulin-like growth factor (IGF) signaling pathway, mediated by insulin receptor substrate (IRS) proteins, is vital for brain development and survival.
- Irs2 signaling specifically regulates peripheral insulin action and pancreatic beta-cell function, with its deficiency leading to diabetes in mice.
Purpose of the Study:
- To investigate the role of Irs2 signaling in the mouse brain.
- To identify a molecular link between diabetes and neurodegenerative disorders.
Main Methods:
- Utilized Irs2 knock-out mouse models.
- Assessed neuronal proliferation during development.
- Examined the hippocampus of aged Irs2 knock-out mice for neurodegenerative markers, specifically phosphorylated tau.
Main Results:
- Disruption of the Irs2 gene led to a 50% reduction in neuronal proliferation during development.
- This disruption dissociated brain growth from Irs1-dependent body growth.
- Accumulation of neurofibrillary tangles containing phosphorylated tau was observed in the hippocampus of old Irs2 knock-out mice.
Conclusions:
- Irs2 signaling plays a critical role in regulating neuronal proliferation and brain development.
- Irs2 signaling exhibits neuroprotective functions, as evidenced by the reduced accumulation of phosphorylated tau.
- Dysregulation of the Irs2 pathway provides a molecular link connecting diabetes and neurodegenerative diseases.