# Mechanistically-Specific Hypotheses: Differential Astrocyte Pathology in PSP vs CBD
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## Hypothesis 1: Astrocyte WNT Tone Determines 4R-Tau Inclusion Morphology
**Mechanism:** Cortical astrocytes exhibit elevated baseline WNT signaling (FZD1/2, DAAM1, DVL1) compared to subcortical astrocytes, maintaining higher β-catenin (CTNNB1) nuclear activity. This WNT-high state drives expression of cytoskeletal regulators (CDC42, RAC1) that favor tau redistribution into distal astroglial processes, producing tufted morphology. Subcortical astrocytes with lower WNT tone retain somatodendritic tau accumulation patterns (astrocytic plaques). The WNT-FZD axis thus acts as a rheostat for 4R-tau inclusion geometry.
**Key Evidence:** WNT signaling components show region-specific expression in human astrocytes (Zhang et al., 2016, PMID 26831569); tufted astrocytes associate with cortical regions in PSP while astrocytic plaques predominate in CBD-affected subcortical structures (Dickson et al., 2007).
**Testable