propose

# Mechanistically-Specific Hypotheses: Aβ-Tau Synergy in Alzheimer's Disease

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## Hypothesis 1: Prion-Like Cross-Seeding via Toxic Oligomer Interfaces

**Title**: Aβ oligomers template tau nucleation

**Mechanism**: Amyloid-β oligomers (particularly dodecameric Aβ*56) expose cryptic β-strand domains that directly interact with tau's R2/R3 microtubule-binding repeat domain, catalyzing conformational conversion into β-sheet-rich nuclei. This cross-seeding bypasses the slow homogeneous nucleation barrier, explaining why Aβ precedes and accelerates tau spreading. The formed tau seeds are then transmitted transsynaptically regardless of ongoing Aβ burden.

**Key Evidence**: 
- Aβ-fibrils accelerate recombinant tau aggregation in vitro (PMID 28504677)
-Human PET imaging demonstrates spatial correlation between early Aβ deposition and subsequent tau spread pattern (PMID 29044071)

**Testable Prediction**: In a mouse model where Aβ is turned off after plaque formation, tau pathology will continue to propagate and spread if Aβ*56 oligomers are removed early—but will plateau if tau seeds have already invaded downstream brain regions.

**Target Gene/Protein**: Aβ*56 oligomer / tau R2 domain interface

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## Hypothesis 2: Kinase-Phosphatase Set-Point Disruption

**Title**: Aβ permanently raises GSK3β activity

**Mechanism**: Aβ42 oligomers trigger persistent activation of GSK3β (via PP2A inhibition and FYN-mediated tyrosine phosphorylation of GSK3β-Y216) while simultaneously inhibiting PP2A through POSTNSA-mediated recruitment. This creates a new kinase-phosphatase equilibrium biased toward tau hyperphosphorylation. Because GSK3β also phosphorylates Aβ-metabolizing enzymes (BACE1, IDE), this circuit generates more Aβ and more phospho-tau in a feed-forward loop.

**Key Evidence**:
- Post-mortem AD brain shows reduced PP2A activity and elevated active GSK3β (PMID 12431986)
- GSK3β inhibition reduces both Aβ and tau pathology in 3xTg mice (PMID 18930951)

**Testable Prediction**: Acute GSK3β inhibition in late-stage 3xTg mice will reduce tau phosphorylation but NOT restore PP2A activity or reduce Aβ—indicating the set-point is locked and requires earlier intervention.

**Target Gene/Protein**: GSK