Verdin, E. — Page 3 | bioRxiv Science

bioRxiv2017

Histone Deacetylase 7 Mediates Tissue-Specific Autoimmunity via Control of Innate Effector Function in Invariant Natural Killer T-Cells

We report that Histone Deacetylase 7 (HDAC7) controls the thymic effector programming of Natural Killer T (NKT) cells, and that interference with this function contributes to tissue-specific autoimmunity. Gain of HDAC7 function in thymocytes blocks both negative selection and NKT development, diverting these cells into a Tconv-like lineage. Conversely, HDAC7 deletion promotes thymocyte apoptosis and causes aberrant expansion of innate-effector cells. Investigating the mechanisms involved, we found that HDAC7 binds PLZF and modulates PLZF-dependent transcription. Moreover, HDAC7 and many of its transcriptional targets are human risk loci for IBD and PSC, autoimmune diseases that strikingly resemble the disease we observe in HDAC7 gain-of-function in mice. Importantly, reconstitution of iNKT cells in these mice abrogated their disease, suggesting that interaction between the defects in negative selection and iNKT cells caused by altered HDAC7 function can cause tissue-restricted autoimmunity, a finding that may explain the association between HDAC7 and hepatobiliary autoimmunity.

immunology↗

bioRxiv2017

Ketogenic diet or BHB improves epileptiform spikes, memory, survival in Alzheimer’s model

Links between epilepsy and Alzheimers disease (AD) are seen in both human patients and mouse models. Human patients with AD may commonly have subclinical epileptiform spikes (EP spikes)1, and overt epilepsy is associated with more rapid cognitive decline2. Mechanistic studies in mouse models of Alzheimers disease (AD) have shown that altered network activity and epileptiform spikes stem from dysfunctional inhibitory interneurons3, which are key elements of cortical circuits underlying cognition4. Treatments that reduce epileptiform spikes improve cognition in these models5,6. Thus, targeting subclinical epileptiform activity may be a promising new therapeutic approach to AD7. Ketogenic diet (KD) has long been used to treat forms of epilepsy8, including Dravet syndrome, a childhood epilepsy caused by mutations in a gene that is critical for inhibitory interneuron function in mouse AD models5,9. However, the concurrent effects of a ketogenic diet on brain electrical activity, cognitive decline, and survival have not been tested, and the translational rationale and feasibility of such an intervention remain uncertain. Here we show that a ketogenic diet reduces epileptiform spikes in the hAPPJ20 mouse model of AD. Similar reduction of EP spikes is observed using a {beta}-hydroxybutyrate (BHB) ester in both AD and Dravet mice. A ketogenic diet improves context-dependent and visuo-spatial learning in hAPPJ20 mice. It also reduces the high seizure-related mortality observed in male mice of this model. Therapies derived from {beta}-hydroxybutyrate may have potential application in ameliorating cognitive dysfunction in AD through reducing subclinical epileptiform activity.

neuroscience↗