Pathological Human Tau Induces Alterations in the Brain Insulin Signaling Cascade

Area of Science:

• Neuroscience
• Molecular Biology
• Endocrinology

Background:

• Alzheimer's disease (AD) involves neurodegeneration linked to impaired neuronal insulin signaling and insulin resistance.
• Type 2 diabetes mellitus (T2DM) correlates with AD, but the underlying mechanisms remain unclear.

Purpose of the Study:

• To investigate the impact of pathological human tau (PH-Tau) expression on neuronal excitability and insulin receptor signaling in a novel mouse model.
• To explore the relationship between PH-Tau, insulin sensitivity, and brain function in the context of neurodegeneration.

Main Methods:

• Developed a PH-Tau transgenic mouse model (PH-Tau-Tg) exhibiting cognitive decline and neurodegeneration.
• Recorded extracellular field potentials in the prefrontal cortex to assess neuronal excitability after insulin and kainic acid (KA) administration.
• Conducted glucose tolerance tests to evaluate insulin sensitivity in PH-Tau-Tg mice.

Main Results:

• PH-Tau-Tg mice displayed increased baseline neuronal excitability, indicated by higher high-frequency brain wave power spectrum densities.
• Insulin administration reduced fast ripples, with a more pronounced effect in PH-Tau-Tg mice.
• KA injection significantly increased neuronal activity in control mice but not in PH-Tau-Tg mice, suggesting altered neuronal response.
• PH-Tau-Tg mice exhibited hyperglycemia and reduced insulin sensitivity, consistent with compensatory upregulation of brain insulin receptors.

Conclusions:

• PH-Tau expression disrupts brain insulin signaling, leading to reduced insulin sensitivity and altered neuronal excitability.
• The brain's insulin signaling pathway is significantly affected in PH-Tau-Tg mice, with exogenous insulin modulating hypersynchronous activity.
• Abnormal tau may exacerbate the neurotoxic environment in Alzheimer's disease by interfering with crucial insulin signaling cascades in the brain.