Lastly, this project has been 8+ years in the making, long before I joined the lab, so there is a really big team to thank, like @geriscidoc.bsky.social, but most are not on Bluesky. And thanks to our funding, especially to the NIA for my recently awarded F99/K00, which made this work possible!
There is a lot more really cool stuff in the paper - diet studies in Tau mice and flies, snRNA-seq, ex vivo hippocampal slice culture, MS-based Tau interactomics - please check it out, and let me know what you think! Excited to get some feedback.
One of the most exciting findings was that R- and S-BHB strengthened Tau interaction with OPTN, a Ub-dependent adaptor for LC3B, which has been shown to play a key role in Tau proteostasis. Long-story short, we found that BHB's action on Tau was dependent on OPTN: loss of OPTN, loss of benefit.
What's more, we found that ketolysis of BHB was dispensable in these effects, as the non-canonical enantiomer S-BHB, which cannot be oxidized by BDH1 for acetyl-CoA and ATP production, recapitulated or even improved upon the benefits of R-BHB.
Next, as neurons are center-stage in the early stages of AD brain metabolic dysfunction, we explored cell-autonomous effects of BHB on neurons. We found that BHB: 1. reduces Tau secretion, 2. improves Tau turnover, and 3. strengthened Tau-protein interactions in the endolysosomal system.
First, contributing to a growing body of work that shows BHB and precursors is a viable therapeutic for numerous neurological disorders, we found that a ketone ester diet reduces pathological Tau, including hyperphosphorylated, insoluble, and seed-forming species, in the PS19 mouse model.
Metabolic interventions that induce ketosis - KDs, CR, IF, exercise - show great promise in the treatment of AD and related dementia. R-BHB, the primary ketone body produced in ketosis, reproduces key features of these interventions, and we wanted to determine how BHB exerts its benefits on Tau.
Excited to share the first big paper from my PhD work, now out on BioRxiv! In this work, we report a novel, ketolysis-independent mechanism of action for beta-hydroxybutyrate (BHB) in AD: BHB improves neuronal Tau proteostasis via LC3B-OPTN-dependent autophagy.
www.biorxiv.org/content/10.6...
congrats!!!
I could not be more excited to have our lab's first story online where we report our discovery that HDACs ~reverse~ their activity to ADD acyl groups to lysine! We found this for our favorite ketone body, BHB, but this pathway controls other lysine modifications too!๐งต
www.nature.com/articles/s41...
excited to see this out! congrats to your team!
