Mammalian target of rapamycin (mTor) mediates tau protein dyshomeostasis: implication for Alzheimer disease

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Aberrant mammalian target of rapamycin (mTor) accumulation is observed in Alzheimer disease (AD) brains.
• mTor signaling, particularly through p70 S6 kinase, is linked to tau hyperphosphorylation and aggregation in AD.

Purpose of the Study:

• To investigate the direct role of active mammalian target of rapamycin (mTor) in Alzheimer disease (AD) pathology.
• To identify specific tau phosphorylation sites mediated by mTor.
• To elucidate the impact of mTor on tau homeostasis and neuronal function.

Main Methods:

• Post-mortem analysis of Alzheimer disease (AD) brains.
• Mass spectrometry and Western blotting to identify tau phosphoepitopes.
• Development of genetically modified SH-SY5Y neuroblastoma cell lines to manipulate mTor activity.
• In vitro and cellular assays to assess tau phosphorylation, synthesis, aggregation, and microtubule stability.

Main Results:

• Active mammalian target of rapamycin (mTor) accumulates in tangle-bearing neurons in early-stage Alzheimer disease (AD) brains.
• Three specific tau phosphoepitopes were identified as directly phosphorylated by mTor.
• mTor activation in cellular models promotes tau synthesis, aggregation, and microtubule destabilization.
• Modulation of mTor activity alters the levels of various tau kinases and phosphatases, disrupting tau homeostasis.

Conclusions:

• Mammalian target of rapamycin (mTor) directly phosphorylates tau at specific sites, contributing to Alzheimer disease (AD) pathology.
• mTor dysregulation disrupts tau homeostasis, leading to neuronal dysfunction and compromised microtubule stability.
• Targeting the mTor pathway represents a potential therapeutic strategy for Alzheimer disease (AD).