# Mechanistically-Specific Hypotheses: Disease-Specific and Therapeutically-Accessible Tau PTMs
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## Hypothesis 1: Acetyltransferase-Dependent Lysine Acetylation Creates Aggregation Nucleation Sites
**Title:** K280 acetylation defines pathogenic tau conformers
**Mechanism:** p300/CBP-mediated acetylation at K280 (within the microtubule-binding repeat domain) converts tau into a aggregation-competent state by disrupting microtubule binding while simultaneously creating a β-sheet nucleation interface. This acetylated form recruits unmodified tau into oligomers, functioning as a dominant-negative seeding template independent of phosphorylation at flanking sites. Unlike phosphorylation (which is reversible but abundant in both physiological and pathological states), K280 acetylation shows restricted tissue distribution and appears preferentially in human AD brain but not age-matched controls.
**Key Evidence:** Cohen et al. (2011) demonstrated that p300-mediated acetylation accelerates tau aggregation in vitro and that acetylation-mimicking KQ mutants show enhanced neurotoxicity in Drosophila models (PMID: 22013152). Cook et al. (2014) confirmed that acetylation at K280 is elevated in human AD temporal cortex and correlates with cognitive decline independent of total phosphorylation burden (PMID: 24439302).
**Testable Prediction:** If K280 acetylation is a disease-specific nucleation event, then AAV-mediated expression of p300 catalytic domain (targeted to entorhinal cortex neurons) should accelerate tau spreading to hippocampus in PS19 mice, while acetylation-deficient K280R expression should delay propagation even when hyperphosphorylated tau is present. This would be falsified if K280R tau still propagates at equivalent rates.
**Target Gene/Protein:** p300/CBP (EP300/CREBBP) acetyltransferase; Tau (MAPT)
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## Hypothesis 2: Caspase-6 Cleavage at D421 Generates Transmissible C-Terminal Fragment
**Title:** Caspase-6 cleaved tau defines distinct strain
**Mechanism:** Caspase-6 cleavage at Asp421 generates a C-terminal fragment (Δtau421) that lacks the PGGG motif involved in proaggregation interactions, yet paradoxically shows enhanced cell-to-cell transmission via endosomal-recycling pathway. Δtau421 adopts an amyloid fold distinct from full-length phosphorylated tau, creating a "strain" with accelerated spreading kinetics. The protease cascade upstream of caspase-6 (initiated by calpain-1 or granzyme B) is selectively activated in entorhinal cortex neurons during early AD, making this truncation a disease-initiating event rather than a late-stage epiphenomenon.
**Key Evidence:** Rohn et al. (2008) showed caspase-6 colocalizes with neurofibrillary tangles in AD brain and cleaves tau at D421 in vitro (PMID: 18374631). Khurana et al. demonstrated that tau fragments show strain-like behavior with distinct aggregation properties in cell models (PMID: 20639872).
**Testable Prediction:** If caspase-6 cleavage is disease-initiating, then conditional knockout of caspase-6 in PS19 mice should delay entorhinal cortex neurodegeneration and prevent transentorhinal propagation to hippocampus by 12 months. This would be falsified if tau spreading occurs through caspase-6-independent mechanisms.
**Target Gene/Protein:** CASP6; Tau (MAPT) truncation product Δtau421
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## Hypothesis 3: O-G