Tau pathology induces intraneuronal cholesterol accumulation.

Area of Science:

• Neuroscience
• Biochemistry
• Genetics

Background:

• Cholesterol metabolism is implicated in Alzheimer disease and Niemann-Pick type C disease, but not frontotemporal dementias.
• Protein tau hyperphosphorylation and neurofibrillary tangle formation occur in these neurodegenerative diseases.
• The relationship between cholesterol and tau pathology requires further elucidation.

Purpose of the Study:

• To investigate the impact of tau pathology on cellular cholesterol homeostasis.
• To explore the potential bidirectional relationship between cholesterol and tau.

Main Methods:

• Utilized mice models expressing P301L mutant human tau (FTDP-17 model).
• Compared sterol levels in tau-burdened neurons versus unaffected neighbors using filipin fluorescence microscopy.
• Examined apolipoprotein E-deficient mice to assess cholesterol transporter influence.

Main Results:

• Neurons with tau pathology exhibited higher cellular unesterified cholesterol levels, independent of apolipoprotein E status.
• This finding suggests tau pathology directly affects cellular cholesterol homeostasis.
• Data indicate a potential impact of tau on brain cholesterol transport and metabolism.

Conclusions:

• Tau pathology influences neuronal cholesterol homeostasis.
• Disturbances in cholesterol metabolism may initiate or exacerbate tau pathology.
• A potential vicious cycle exists where cholesterol dysregulation and tau pathology mutually promote neurofibrillary tangle formation.