HS3ST2 expression induces the cell autonomous aggregation of tau

Area of Science:

• Neuroscience
• Biochemistry
• Cell Biology

Background:

• Heparan sulfates (HS) accumulate intracellularly in Alzheimer's disease (AD) neurons, co-localizing with tau protein tangles.
• The precise role and consequences of HS accumulation in AD pathogenesis remain unclear.
• Previous work identified HS3ST2 as critical for abnormal tau phosphorylation in AD-related tauopathy.

Purpose of the Study:

• To investigate whether HS3ST2 expression induces intracellular tau aggregation.
• To determine if HS3ST2-mediated tau aggregation is cell-autonomous.
• To establish cellular models mimicking AD-related HS accumulation and tau aggregation.

Main Methods:

• Engineered HEK293 cells for stable expression of HS3ST2 and human tau (wild-type or P301S mutant) using pEBV plasmids.
• Utilized cell models to observe tau phosphorylation and aggregation.
• Analyzed intracellular HS accumulation and tau aggregation patterns.

Main Results:

• HS3ST2 gain of function induced cell-autonomous tau aggregation.
• Tau aggregation occurred in cells expressing both wild-type tau and tau with the P301S mutation.
• The engineered cells successfully mimicked intracellular HS accumulation and tau aggregation seen in AD and tauopathy.

Conclusions:

• Neural HS3ST2 plays a critical role in the cell-autonomous self-aggregation of tau.
• HS3ST2 is a key factor in the pathogenesis of tauopathies, including Alzheimer's disease.
• Targeting HS3ST2 may offer a therapeutic strategy for tauopathies.