Extracellular Tau Oligomers Damage the Axon Initial Segment.

Area of Science:

• Neuroscience
• Cell Biology
• Neurodegenerative Diseases

Background:

• Alzheimer's disease (AD) is characterized by compromised neuronal polarity and synaptic connectivity.
• The axon initial segment (AIS) is crucial for neuronal polarity and function, regulating protein segregation and action potential initiation.
• Extracellular tau oligomers (xcTauOs) spread pathology via a prion-like mechanism, but their broader cellular effects are less understood.

Purpose of the Study:

• To investigate the hypothesis that AIS structure is sensitive to extracellular tau oligomers (xcTauOs).

Main Methods:

• Primary cortical neurons from wild-type (WT) and tau knockout (KO) mice were treated with xcTauOs.
• Quantitative western blotting and immunofluorescence microscopy were used to assess AIS proteins, including TRIM46.
• Human hippocampal tissues from AD and age-matched non-AD donors were analyzed for AIS protein composition and length.

Main Results:

• xcTauOs reduced TRIM46 concentration and shortened the AIS in cultured WT neurons, but not in tau KO neurons.
• Lentiviral tau expression in KO neurons restored AIS sensitivity to xcTauOs.
• In AD human hippocampus, neurons with neurofibrillary tangles showed reduced AIS TRIM46 concentration and length, despite unchanged overall AIS protein levels.

Conclusions:

• Extracellular tau oligomers induce partial AIS damage in cultured neurons through an intracellular tau-dependent mechanism.
• This suggests xcTauOs may contribute to AIS reduction in AD neurons in vivo by interacting with endogenous tau.