Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer’s disease (AD)1. The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge2. Here, we show that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible. This blockade is mediated by histone deacetylase (HDAC) 2, which is increased by AD-related neurotoxic insults in vitro, in two mouse models of neurodegeneration, and in AD patients. HDAC2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concomitant decrease in expression. Importantly, reversing the buildup of HDAC2 by shRNA-mediated knockdown unlocks the repression of these genes, re-instates structural and synaptic plasticity, and abolishes neurodegeneration-associated memory impairments. These findings advocate for the development of HDAC2-selective inhibitors, and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade.

Summary Traumatic events generate some of the most enduring forms of memories. Despite the elevated lifetime prevalence of anxiety disorders, effective strategies to attenuate long-term traumatic memories are scarce. The most efficacious treatments to diminish recent (i.e., day-old) traumata capitalize on memory updating mechanisms during reconsolidation that are initiated upon memory recall. Here, we show that, in mice, successful reconsolidation-updating paradigms for recent memories fail to attenuate remote (i.e., month-old) ones. We find that, whereas recent memory recall induces a limited period of hippocampal neuroplasticity mediated, in part, by S-nitrosylation of HDAC2 and histone acetylation, such plasticity is absent for remote memories. However, by using an HDAC2-targeting inhibitor (HDACi) during reconsolidation, even remote memories can be persistently attenuated. This intervention epigenetically primes the expression of neuroplasticity-related genes, which is accompanied by higher metabolic, synaptic, and structural plasticity. Thus, applying HDACis during memory reconsolidation might constitute a treatment option for remote traumata.

Caloric restriction (CR) is a dietary regimen known to promote lifespan by slowing down the occurrence of age-dependent diseases. The greatest risk factor for neurodegeneration in the brain is age, from which follows that CR might also attenuate the progressive loss of neurons that is often associated with impaired cognitive capacities. In this study, we used a transgenic mouse model that allows for a temporally and spatially controlled onset of neurodegeneration to test the potentially beneficial effects of CR. We found that in this model, CR significantly delayed the onset of neurodegeneration, synaptic loss and dysfunction, and thereby preserved cognitive capacities. Mechanistically, CR induced the expression of the known lifespan-regulating protein SIRT1, prompting us to test whether a pharmacological activation of SIRT1 might recapitulate CR. We found that oral administration of a SIRT1-activating compound essentially replicated the beneficial effects of CR. Thus, SIRT1-activating compounds might provide a pharmacological alternative to the regimen of CR against neurodegeneration and its associated ailments.

Background Immune checkpoints including programmed death-ligand 1/programmed death-1/ (PD-L1/PD-1), cytotoxic T lymphocyte antigen 4 (CTLA-4), and indolaimine-2, 3-deoxygenase (IDO) have recently emerged as effective candidates for treatment against a range of human malignancies. We have investigated their expression in the uterine mesenchymal tumors. Methods Sixty-eight mesenchymal tumors were categorized into 6 diagnostic groups. We assessed PD-L1, PD-1, CTLA-4, and IDO expression on paraffin embedded tissue blocks of the uterine tumors using the respective antibodies. Immunohistochemical (IHC) stains were classified as positive when the reactions were present in at least 1% of the cell membranes for PD-L1/PD-1 or in cytoplasm for CTLA-4 and IDO, regardless of intensity. Student’s t-test and McNemar’s chi-square tests were carried out to analyze the results. Results The mesenchymal neoplasms had expressed the immune checkpoints in the tumor and/or the lymphoid cells at the rate of 49% and 54% respectively. The tumor cells were positive in 10 (18%, PD-L1), 0 (0%, PD-1), 18 (32%, CTLA-4), and 13 (23%, IDO) cases while the infiltrating lymphoid cells were positive in 10 (18%, PD-L1), 23 (40%, PD-1), 18 (32%, CTLA-4), and 13 (23%, IDO) cases. Overall, comparison of paired tumor vs lymphoid cells resulted in p-values of ≤ 0.04. Conclusions Nearly 50% of the uterine tumors express at least one of the immune checkpoints in tumor and/or the infiltrating lymphoid cells. However, expression of the proteins in the two cellular components are mutually exclusive. Namely, when tumor cells express an immune checkpoint, the infiltrating lymphoid cells do not, and vice versa. Since the leiomyosarcomas are reportedly resistant to the immunotherapy when PD-L1 is expressed in the tumor cells, it can be posited that presence of the IHC positive lymphoid cells may be a better indicator of response to the treatment.

Objectives. Fibroblast activation protein alpha (FAP) is highly expressed by cancer-associated fibroblasts in multiple epithelial cancers. The aim of this study was to characterize FAP expression in sarcomas to explore its potential utility as a diagnostic and therapeutic target and prognostic biomarker in sarcomas. Methods. Available tissue samples from patients with bone or soft tissue tumors were identified at the University of California, Los Angeles. FAP expression was evaluated via immunohistochemistry (IHC) in tumor samples (n = 63), adjacent normal tissues (n = 30), and positive controls (n = 2) using semiquantitative systems for intensity (0 = negative; 1 = weak; 2 = moderate; and 3 = strong) and density (none, <25%, 25–75%; >75%) in stromal and tumor/nonstromal cells and using a qualitative overall score (not detected, low, medium, and high). Additionally, RNA sequencing data in publicly available databases were utilized to compare FAP expression in samples (n = 10,626) from various cancer types and evaluate the association between FAP expression and overall survival (OS) in sarcoma (n = 168). Results. The majority of tumor samples had FAP IHC intensity scores ≥2 and density scores ≥25% for stromal cells (77.7%) and tumor cells (50.7%). All desmoid fibromatosis, myxofibrosarcoma, solitary fibrous tumor, and undifferentiated pleomorphic sarcoma samples had medium or high FAP overall scores. Sarcomas were among cancer types with the highest mean FAP expression by RNA sequencing. There was no significant difference in OS in patients with sarcoma with low versus high FAP expression. Conclusion. The majority of the sarcoma samples showed FAP expression by both stromal and tumor/nonstromal cells. Further investigation of FAP as a potential diagnostic and therapeutic target in sarcomas is warranted.