Spreading of Tau Protein Does Not Depend on Aggregation Propensity

Area of Science:

• Neuroscience
• Pathology
• Molecular Biology

Background:

• Alzheimer disease (AD) progression is stereotypically linked to Tau pathology spreading.
• The mechanisms of Tau spreading, including prion-like templated aggregation, remain debated.
• The relationship between Tau aggregation propensity and its spreading capability is not fully understood.

Purpose of the Study:

• To investigate if Tau's aggregation propensity correlates with its synaptic spreading and pathology propagation.
• To examine Tau protein propagation in brain regions relevant to Alzheimer disease.
• To elucidate the cellular mechanisms underlying Tau spreading and aggregation.

Main Methods:

• Utilized mice expressing full-length human Tau with pro-aggregant (TauΔK) or anti-aggregant (TauΔK-PP) mutations in the entorhinal cortex (EC).
• Employed adeno-associated virus (AAV) vectors to enhance Tau expression in the EC.
• Analyzed brain tissues using immunohistological and biochemical methods to detect Tau propagation and pathological changes.

Main Results:

• Low levels of TauΔK and TauΔK-PP showed similar distribution in EC neurons and projections, independent of aggregation propensity.
• Increased Tau expression led to local Tau misfolding, synaptotoxicity, and astrogliosis in EC neurons.
• A low level of trans-neuronal Tau propagation was observed, but it did not involve pathological phosphorylation or misfolding, nor was it dependent on Tau's aggregation propensity.

Conclusions:

• Tau spreading and pathology in the entorhinal cortex are concentration-dependent, not aggregation-dependent.
• Increased Tau expression can induce local misfolding, synaptotoxicity, and astrogliosis.
• Trans-neuronal spreading of Tau occurs at low levels but does not involve templated misfolding in recipient neurons.