Tau Secretion and Propagation Is Regulated by p300/CBP via Autophagy-Lysosomal Pathway in Tauopathy

Abstract

ManuscriptChen et al. / 2 SUMMARY The trans-neuronal propagation of tau has been implicated in the progression of tau-mediated neurodegeneration. Tau secretion from neurons is the first step in tau transmission, but little is known about the cellular mechanism. Here, we report that p300/CBP, the lysine acetyltransferase that acetylates tau and regulates its homeostasis and toxicity, serves as a key regulator of tau secretion by inhibiting the autophagy-lysosomal pathway (ALP). Increased p300/CBP activity was associated with impaired function of this pathway in a tau transgenic mouse model. p300/CBP hyperactivation increased tau secretion by blocking autophagic flux. Conversely, inhibiting p300/CBP genetically or pharmacologically promoted autophagic flux, and reduced tau accumulation, tau secretion, and tau propagation in fibril-induced tau spreading models in vitro and in vivo. Our findings show that p300/CBP-induced impairment in the ALP underlies excessive unconventional secretion and pathogenic spread of tau.Chen et al. / 3 particles) of AAV1 expressing either Cre or GFP control (ViroTek), into the dentate gyrus of right hippocampus. 2 μL of synthetic tau fibrils (K18/PL) was injected into CA1 region of left hippocampus. The following coordinates were used for dentate gyrus (anterior-posterior -2.1, medial-lateral -1.7, dorsal-ventral -2.1) and CA1 (anterior-posterior -2.5, medial-lateral +2.0, dorsal-ventral -1.8). Control animals were injected with 2 μL of PBS instead of fibril. StatisticsData were analyzed with GraphPad Prism 7 (GraphPad) or Stata. Differences between means were assessed with paired or unpaired Student's t test, one-way or two-way analysis of variance, followed by post hoc testing of pairwise comparisons among genotypes (with Tukey's or Dunnett's correction for one-way ANOVA and Bonferroni correction for two-way ANOVA), or by mixed effects model, as indicated. Pearson's correlation coefficients were used to quantify the linear relationship between two variables. Outliers are pre-established as data outside of mean ± 2SD.

Immunotherapy Against Acetylated Tau at K280 Ameliorates Behavioral Impairments and Pathologies of Tau Transgenic Mouse

“…Phosphorylated p300, the active form of p300, was observed in neurites and cytoplasm of neurons in AD hippocampus and frontal cortex (Wong et al, 2013;Aubry et al, 2015). Pathological activation of p300 inhibits autophagic ux leading to increased tau secretion (Chen et al, 2018). In AD brains, this may aggravate the pathological secretion and propagation of K280-acetylated tau.…”