No abstract

Evidence indicates that tau hyper-phosphorylation and subsequent neurofibrillary tangle formation contribute to the extensive neuronal death in Alzheimer’s disease (AD) and related tauopathies. Recent work has identified that increased tau acetylation can promote tau phosphorylation. Tau acetylation occurs at lysine 280 resulting from increased expression of the lysine acetyltransferase p300. The exact upstream mechanisms mediating p300 expression remain elusive. Additional work highlights the role of the epigenome in tau pathogenesis, suggesting that dysregulation of epigenetic proteins may contribute to acetylation and hyper-phosphorylation of tau. Here, we identify and focus on the histone-binding subunit of the Nucleosome Remodeling and Deacetylase (NuRD) complex: Retinoblastoma-Binding Protein 7 (Rbbp7). Rbbp7 chaperones chromatin remodeling proteins to their nuclear histone substrates, including histone acetylases and deacetylases. Notably, Rbbp7 binds to p300, suggesting that it may play a role in modulating tau acetylation. We interrogated Rbbp7 in post-mortem brain tissue, cell lines and mouse models of AD. We found reduced Rbbp7 mRNA expression in AD cases, a significant negative correlation with CERAD (neuritic plaque density) and Braak Staging (pathogenic tau inclusions) and a significant positive correlation with post-mortem brain weight. We also found a neuron-specific downregulation of Rbbp7 mRNA in AD patients. Rbbp7 protein levels were significantly decreased in 3xTg-AD and PS19 mice compared to NonTg, but no decreases were found in APP/PS1 mice that lack tau pathology. In vitro, Rbbp7 overexpression rescued TauP301L-induced cytotoxicity in immortalized hippocampal cells and primary cortical neurons. In vivo, hippocampal Rbbp7 overexpression rescued neuronal death in the CA1 of PS19 mice. Mechanistically, we found that increased Rbbp7 reduced p300 levels, tau acetylation at lysine 280 and tau phosphorylation at AT8 and AT100 sites. Collectively, these data identify a novel role of Rbbp7, protecting against tau-related pathologies, and highlight its potential as a therapeutic target in AD and related tauopathies.

Mpox is a new public health outbreak that particularly threatens the homeless population. Street Medicine Phoenix (SMP) is a student-led interprofessional volunteer organization that provides medical care and other essential services to individuals experiencing homelessness in Phoenix, Arizona. In addition to core services such as wound care; health screenings (blood pressure and blood glucose.); vision screenings; HIV testing; naloxone education and distribution; flu, COVID-19, and Hepatitis A vaccinations; and community resource referrals, SMP began offering mpox education and vaccination at outreach events. During an outreach event shortly after the onset of the mpox outbreak, SMP identified 2 suspected mpox cases. Accordingly, SMP has partnered with the Maricopa County Public Health Department to set up mobile mpox vaccination clinics on the streets outside of Phoenix Arizona’s largest homeless shelter. We share the details of these 2 cases along with our early efforts vaccinating individuals experiencing homelessness for mpox via our mobile vaccination clinic. Our experiences demonstrate the importance of community agencies providing direct outreach to underserved populations where they are at, particularly the homeless population, to address public health concerns such as emerging disease outbreaks like mpox. In addition, these cases highlight the potential significant impact that street medicine programs can have on their respective homeless communities in the context of infectious disease mitigation and emphasize the importance of partnerships with local health departments.