Effectiveness of Extrafine Single Inhaler Triple Therapy in Chronic Obstructive Pulmonary Disease (COPD) in Germany - The TriOptimize Study.

Purpose: Real-word evidence on the effectiveness of switching from dual therapies or triple therapies (multiple inhalers) to extrafine single-inhaler triple therapy (efSITT), which consists of the inhaled corticosteroid (ICS) beclomethasone, the long-acting ß2-agonist (LABA) formoterol and the long-acting muscarinic antagonist (LAMA) glycopyrronium, in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) is limited. The impact of switching to efSITT on health-related quality of life (HRQoL), COPD specific symptoms, lung function and treatment adherence were assessed in routine clinical care. Patients and Methods: Patients were recruited at 148 sites in Germany between 2017 and 2020 in this multicenter, non-interventional observational study. Demographics, clinical data and treatment history were collected at baseline. HRQoL (measured by COPD Assessment Test [CAT]), lung function and adherence (measured by Test of Adherence to Inhalers [TAI]) were assessed at baseline and after six months. Descriptive analyses were conducted by prior treatment and GOLD groups as well as for the overall population. Results: 55.1% of the 2623 included patients were male. Mean age was 65.8 years. 57.5% of the patients were previously treated with ICS+LABA+LAMA (multiple inhalers), 23.9% with ICS/LABA (single or two inhalers) and 18.6% with LAMA/LABA (single or two inhalers). After six months, largest mean improvements in the total CAT score were observed in the ICS/LABA (-3.9) and LAMA/LABA (-3.9) prior treatment groups as well as in patients in GOLD group B (-2.9). In the overall population, the CAT items for cough, phlegm, and dyspnea decreased on average by -0.4 points each. After six months, FEV1 increased by 2.0 percentage points in relation to predicted values. The percentages of measured sRtot and RV of predicted values decreased by 24.5 and 4.4 percentage points, respectively. The percentage of patients with good adherence increased from 67.8% to 76.5%. Conclusion: Treatment switch to efSITT resulted in an improvement of HRQoL, COPD specific symptoms, lung function parameters and adherence under real-world conditions.

Formin 2 links neuropsychiatric phenotypes at young age to an increased risk for dementia.

Age-associated memory decline is due to variable combinations of genetic and environmental risk factors. How these risk factors interact to drive disease onset is currently unknown. Here we begin to elucidate the mechanisms by which post-traumatic stress disorder (PTSD) at a young age contributes to an increased risk to develop dementia at old age. We show that the actin nucleator Formin 2 (Fmn2) is deregulated in PTSD and in Alzheimer's disease (AD) patients. Young mice lacking the Fmn2 gene exhibit PTSD-like phenotypes and corresponding impairments of synaptic plasticity, while the consolidation of new memories is unaffected. However, Fmn2 mutant mice develop accelerated age-associated memory decline that is further increased in the presence of additional risk factors and is mechanistically linked to a loss of transcriptional homeostasis. In conclusion, our data present a new approach to explore the connection between AD risk factors across life span and provide mechanistic insight to the processes by which neuropsychiatric diseases at a young age affect the risk for developing dementia.

HDAC1 links early life stress to schizophrenia-like phenotypes.

Schizophrenia is a devastating disease that arises on the background of genetic predisposition and environmental risk factors, such as early life stress (ELS). In this study, we show that ELS-induced schizophrenia-like phenotypes in mice correlate with a widespread increase of histone-deacetylase 1 (Hdac1) expression that is linked to altered DNA methylation. Hdac1 overexpression in neurons of the medial prefrontal cortex, but not in the dorsal or ventral hippocampus, mimics schizophrenia-like phenotypes induced by ELS. Systemic administration of an HDAC inhibitor rescues the detrimental effects of ELS when applied after the manifestation of disease phenotypes. In addition to the hippocampus and prefrontal cortex, mice subjected to ELS exhibit increased Hdac1 expression in blood. Moreover, Hdac1 levels are increased in blood samples from patients with schizophrenia who had encountered ELS, compared with patients without ELS experience. Our data suggest that HDAC1 inhibition should be considered as a therapeutic approach to treat schizophrenia.

Histone-acetylation: a link between Alzheimer's disease and post-traumatic stress disorder?

The orchestration of gene-expression programs is essential for cellular homeostasis. Epigenetic processes provide to the cell a key mechanism that allows the regulation of gene-expression networks in response to environmental stimuli. Recently epigenetic mechanisms such as histone-modifications have been implicated with cognitive function and altered epigenome plasticity has been linked to the pathogenesis of neurodegenerative and neuropsychiatric diseases. Thus, key regulators of epigenetic gene-expression have emerged as novel drug targets for brain diseases. Numerous recent review articles discuss in detail the current findings of epigenetic processes in brain diseases. The aim of this article is not to give yet another comprehensive overview of the field but to specifically address the question why the same epigenetic therapies that target histone-acetylation may be suitable to treat seemingly different diseases such as Alzheimer's disease and post-traumatic stress disorder.

K-Lysine acetyltransferase 2a regulates a hippocampal gene expression network linked to memory formation.

Neuronal histone acetylation has been linked to memory consolidation, and targeting histone acetylation has emerged as a promising therapeutic strategy for neuropsychiatric diseases. However, the role of histone-modifying enzymes in the adult brain is still far from being understood. Here we use RNA sequencing to screen the levels of all known histone acetyltransferases (HATs) in the hippocampal CA1 region and find that K-acetyltransferase 2a (Kat2a)--a HAT that has not been studied for its role in memory function so far--shows highest expression. Mice that lack Kat2a show impaired hippocampal synaptic plasticity and long-term memory consolidation. We furthermore show that Kat2a regulates a highly interconnected hippocampal gene expression network linked to neuroactive receptor signaling via a mechanism that involves nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). In conclusion, our data establish Kat2a as a novel and essential regulator of hippocampal memory consolidation.

Histone-methyltransferase MLL2 (KMT2B) is required for memory formation in mice.

The consolidation of long-term memories requires differential gene expression. Recent research has suggested that dynamic changes in chromatin structure play a role in regulating the gene expression program linked to memory formation. The contribution of histone methylation, an important regulatory mechanism of chromatin plasticity that is mediated by the counteracting activity of histone-methyltransferases and histone-demethylases, is, however, not well understood. Here we show that mice lacking the histone-methyltransferase myeloid/lymphoid or mixed-lineage leukemia 2 (mll2/kmt2b) gene in adult forebrain excitatory neurons display impaired hippocampus-dependent memory function. Consistent with the role of KMT2B in gene-activation DNA microarray analysis revealed that 152 genes were downregulated in the hippocampal dentate gyrus region of mice lacking kmt2b. Downregulated plasticity genes showed a specific deficit in histone 3 lysine 4 di- and trimethylation, while histone 3 lysine 4 monomethylation was not affected. Our data demonstrates that KMT2B mediates hippocampal histone 3 lysine 4 di- and trimethylation and is a critical player for memory formation.

HDAC1 regulates fear extinction in mice.

Histone acetylation has been implicated with the pathogenesis of neuropsychiatric disorders and targeting histone deacetylases (HDACs) using HDAC inhibitors was shown to be neuroprotective and to initiate neuroregenerative processes. However, little is known about the role of individual HDAC proteins during the pathogenesis of brain diseases. HDAC1 was found to be upregulated in patients suffering from neuropsychiatric diseases. Here, we show that virus-mediated overexpression of neuronal HDAC1 in the adult mouse hippocampus specifically affects the extinction of contextual fear memories, while other cognitive abilities were unaffected. In subsequent experiments we show that under physiological conditions, hippocampal HDAC1 is required for extinction learning via a mechanism that involves H3K9 deacetylation and subsequent trimethylation of target genes. In conclusion, our data show that hippocampal HDAC1 has a specific role in memory function.

microRNA-34c is a novel target to treat dementias.

MicroRNAs are key regulators of transcriptome plasticity and have been implicated with the pathogenesis of brain diseases. Here, we employed massive parallel sequencing and provide, at an unprecedented depth, the complete and quantitative miRNAome of the mouse hippocampus, the prime target of neurodegenerative diseases such as Alzheimer's disease (AD). Using integrative genetics, we identify miR-34c as a negative constraint of memory consolidation and show that miR-34c levels are elevated in the hippocampus of AD patients and corresponding mouse models. In line with this, targeting miR-34 seed rescues learning ability in these mouse models. Our data suggest that miR-34c could be a marker for the onset of cognitive disturbances linked to AD and indicate that targeting miR-34c could be a suitable therapy.

The anaphase promoting complex is required for memory function in mice.

Learning and memory processes critically involve the orchestrated regulation of de novo protein synthesis. On the other hand it has become clear that regulated protein degradation also plays a major role in neuronal plasticity and learning behavior. One of the key pathways mediating protein degradation is proteosomal protein destruction. The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that targets proteins for proteosomal degradation by the 26S proteasome. While the APC/C is essential for cell cycle progression it is also expressed in postmitotic neurons where it has been implicated with axonal outgrowth and neuronal survival. In this study we addressed the role of APC/C in learning and memory function by generating mice that lack the essential subunit APC2 from excitatory neurons of the adult forebrain. Those animals are viable but exhibit a severe impairment in the ability to extinct fear memories, a process critical for the treatment of anxiety diseases such as phobia or post-traumatic stress disorder. Since deregulated protein degradation and APC/C activity has been implicated with neurodegeneration we also analyzed the effect of Apc2 deletion in a mouse model for Alzheimer's disease. In our experimental setting loss of APC2 form principle forebrain neurons did not affect the course of pathology in an Alzheimer's disease mouse model. In conclusion, our data provides genetic evidence that APC/C activity in the adult forebrain is required for cognitive function.

Altered histone acetylation is associated with age-dependent memory impairment in mice.

As the human life span increases, the number of people suffering from cognitive decline is rising dramatically. The mechanisms underlying age-associated memory impairment are, however, not understood. Here we show that memory disturbances in the aging brain of the mouse are associated with altered hippocampal chromatin plasticity. During learning, aged mice display a specific deregulation of histone H4 lysine 12 (H4K12) acetylation and fail to initiate a hippocampal gene expression program associated with memory consolidation. Restoration of physiological H4K12 acetylation reinstates the expression of learning-induced genes and leads to the recovery of cognitive abilities. Our data suggest that deregulated H4K12 acetylation may represent an early biomarker of an impaired genome-environment interaction in the aging mouse brain.