IF combined treatment with C381 (10 mg/kg i.p., daily, commencing at 9 months of age) and a single intracerebroventricular injection of AAV9 encoding the S142A/S211A phospho-dead constitutively active TFEB variant (1×10¹¹ vg, delivered 72 hours prior to the first C381 dose to allow transgene expression onset) is administered to male and female PS19 (P301S) tau transgenic mice at 9 months of age — a stage characterized by established neurofibrillary tangle burden, synaptic loss, and progressive hippocampal and cortical neurodegeneration — and sustained for 8 weeks,

THEN a synergistic reduction in AT8-positive (Ser202/Thr205) and PHF1-positive (Ser396/Ser404) hyperphosphorylated tau immunoreactivity of ≥50% beyond either monotherapy alone in hippocampal CA1, entorhinal cortex, and amygdala will be observed, accompanied by a ≥30% rescue of NeuN-positive neuron counts relative to vehicle-treated PS19 controls, a measurable reduction in Thioflavin-S-positive neurofibrillary tangles, and improvement in hippocampus-dependent behavioral performance (Barnes maze, contextual fear conditioning), all compared to either monotherapy arm and vehicle control,

BECAUSE the following mechanistic chain unfolds:

1. At 9 months, PS19 hippocampal and cortical neurons harbor a pathological deficit in v-ATPase assembly and proton-pumping activity, causing de-acidification of the lysosomal lumen (pH rising from ~4.5 toward ~6.0), which renders cathepsin B, D, and L proteases hypoactive and creates an autophagic gridlock in which autophagosomes laden with tau oligomers and aggregates stall without productive fusion and degradation. (C381 directly activates v-ATPase and restores lysosomal acidification in models of Parkinson's disease and progranulin deficiency)[https://pmc.ncbi.nlm.nih.gov/articles/PMC8931323/]

2. C381 (10 mg/kg i.p.), a small-molecule v-ATPase activator with demonstrated CNS penetrance, directly re-acidifies existing neuronal lysosomes by stabilizing v-ATPase V0–V1 domain assembly and restoring proton gradient, thereby reactivating cathepsin-dependent proteolytic capacity in lysosomes already present in affected neurons within hours of administration. (C381 restores lysosomal acidification and v-ATPase activity in neurodegenerative disease models)[https://pmc.ncbi.nlm.nih.gov/articles/PMC8931323/]

3. Simultaneously, AAV9-TFEB(S142A/S211A) — constitutively nuclear due to abolished mTORC1-mediated phosphorylation at Ser142 and Ser211, which normally creates 14-3-3 binding sites and retains TFEB in the cytoplasm — drives transcriptional upregulation of the full CLEAR (Coordinated Lysosomal Expression and Regulation) network, including LAMP1, LAMP2, MCOLN1, ATP6V1A, CTSB, CTSD, BECN1, SQSTM1/p62, and MAP1LC3B, expanding the total number of lysosomes and autophagosomes per neuron. (TFEB overexpression selectively clears aberrant tau and rescues neurotoxicity in tauopathy models, as reviewed in the Evidence Set from EMBO Molecular Medicine, 2014)

4. **[...

SENS category: LysoSENS