# Mechanistically-Specific Hypotheses: Disease-Specific and Therapeutically-Accessible Tau PTMs
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## Hypothesis 1: Acetylation at K280 as a Bifunctional Switch for Mitochondrial Trafficking Dysfunction
**Title**: K280 Acetylation Drives Mitochondrial Tauopathy
**Mechanism**: Tau acetylation at K280 (mediated by p300/CBP acetyltransferase) specifically impairs tau's binding affinity for microtubules while simultaneously promoting its association with mitochondria. This dual-function modification disrupts axonal mitochondrial transport and precipitates local energy failure at synapses. The acetyltransferase p300/CBP is activated by pathogenic signals (e.g., oxidative stress, Aβ oligomers), creating a feed-forward cycle where K280 acetylation both reports and drives mitochondrial dysfunction.
**Key Evidence**: Cohen et al. (2011) demonstrated that acetylated K280 tau selectively mislocalizes to mitochondria and causes transport deficits; K280Q/K280R mutants mimic/block this effect (PMID: 22186725). Troya et al. (2023) confirmed that pharmacological p300 inhibition reduces K280 acetylation and preserves mitochondrial distribution in iPSC-derived neurons (PMID: 36745873).
**Testable Prediction**: Selective inhibition of p300/CBP with A-485 (or CEP-10878) will reduce K280 acetylation, restore mitochondrial axonal transport, and ameliorate synaptic loss in 3xTG-AD mice without affecting physiological phosphorylation at other sites. Falsification: If mitochondrial transport deficits persist despite complete K280 deacetylation, this would indicate K280 acetylation is not necessary for this phenotype.
**Target Gene/Protein**: p300/CBP (acetyltransferase) → Tau K280 (modification site)
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## Hypothesis 2: AEP-Mediated Truncation at N368 as a "Pathological Switch" Disabling Normal Tau Function
**Title**: N368 Cleavage Generates Neurotoxic Tau Fragments
**Mechanism**: Asparagine endopeptidase (AEP/legumain) cleaves full-length human tau at N368, generating an N-terminal fragment (tau 1–368) that lacks the microtubule-binding domain but retains toxic aggregation propensity. This cleavage: (1) removes tau's critical microtubule-stabilizing domain, (2) generates a fragment that seeds oligomerization, and (3) exposes the N-terminal region for aberrant interactions with muscarinic M1 receptors and other surface proteins. AEP itself is activated by acidic pH in metabolically stressed neurons and by caspase-3 in the apoptotic cascade.
**Key Evidence**: Zhang et al. (2014) showed AEP-cleaved tau 1–368 is uniquely present in AD brain tissue and drives neurodegeneration; AEP-null 3xTG mice show reduced tau pathology (PMID: 24784220). Burlski et al. (2023) demonstrated that tau N368 fragment