Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms

Area of Science:

• Neuroscience
• Pathology
• Endocrinology

Background:

• Alzheimer's disease (AD) is characterized by hyperphosphorylated tau protein in neurofibrillary tangles.
• Aging is the primary risk factor for late-onset AD.
• Insulin resistance, impaired glucose tolerance, and diabetes mellitus (DM) are common in the elderly and linked to AD.

Purpose of the Study:

• To investigate if insulin dysfunction promotes tau pathology.
• To explore the mechanisms by which insulin dysfunction affects tau.

Main Methods:

• Induced insulin deficiency and DM in mice using streptozotocin (STZ).
• Monitored tau phosphorylation levels, tau aggregation, body temperature, and beta-amyloid (Abeta) precursor protein (APP) levels over time.
• Assessed cellular protein phosphatase 2A activity.

Main Results:

• STZ-induced insulin deficiency caused mild to massive tau hyperphosphorylation in mice.
• Hyperphosphorylated tau localized to axons and neuropil, preventing microtubule binding but not causing aggregation.
• A decrease in cellular protein phosphatase 2A activity was observed, alongside hypothermia-induced effects.

Conclusions:

• Insulin dysfunction induces abnormal tau hyperphosphorylation through temperature-dependent (hypothermia) and temperature-independent (phosphatase inhibition) mechanisms.
• These findings highlight a potential link between metabolic disorders like DM and AD pathogenesis.
• Targeting insulin signaling or related pathways may offer therapeutic strategies for AD.