Dataset Information

Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations.

ABSTRACT: Transcription disequilibria are characteristic of many neurodegenerative diseases. The activity-evoked transcription of immediate early genes (IEGs), important for neuronal plasticity, memory and behavior, is altered in CNS diseases and governed by epigenetic modulation. KDM1A, a histone 3 lysine 4 demethylase that forms part of transcription regulation complexes, has been implicated in the control of IEG transcription. Here we report the development of vafidemstat (ORY-2001), a brain penetrant inhibitor of KDM1A and MAOB. ORY-2001 efficiently inhibits brain KDM1A at doses suitable for long term treatment, and corrects memory deficit as assessed in the novel object recognition testing in the Senescence Accelerated Mouse Prone 8 (SAMP8) model for accelerated aging and Alzheimer's disease. Comparison with a selective KDM1A or MAOB inhibitor reveals that KDM1A inhibition is key for efficacy. ORY-2001 further corrects behavior alterations including aggression and social interaction deficits in SAMP8 mice and social avoidance in the rat rearing isolation model. ORY-2001 increases the responsiveness of IEGs, induces genes required for cognitive function and reduces a neuroinflammatory signature in SAMP8 mice. Multiple genes modulated by ORY-2001 are differentially expressed in Late Onset Alzheimer's Disease. Most strikingly, the amplifier of inflammation S100A9 is highly expressed in LOAD and in the hippocampus of SAMP8 mice, and down-regulated by ORY-2001. ORY-2001 is currently in multiple Phase IIa studies.

SUBMITTER: Maes T

PROVIDER: S-EPMC7259601 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations.

Maes Tamara T Mascaró Cristina C Rotllant David D Lufino Michele Matteo Pio MMP Estiarte Angels A Guibourt Nathalie N Cavalcanti Fernando F Griñan-Ferré Christian C Pallàs Mercè M Nadal Roser R Armario Antonio A Ferrer Isidro I Ortega Alberto A Valls Nuria N Fyfe Matthew M Martinell Marc M Castro Palomino Julio César JC Buesa Arjol Carlos C

PloS one 20200529 5

Transcription disequilibria are characteristic of many neurodegenerative diseases. The activity-evoked transcription of immediate early genes (IEGs), important for neuronal plasticity, memory and behavior, is altered in CNS diseases and governed by epigenetic modulation. KDM1A, a histone 3 lysine 4 demethylase that forms part of transcription regulation complexes, has been implicated in the control of IEG transcription. Here we report the development of vafidemstat (ORY-2001), a brain penetrant ...[more]

PMID: 32469975

Similar Datasets

Project description:BACKGROUND:Early life anesthesia exposure results in long-term cognitive deficits in rats. Environmental enrichment consisting of social housing, a stimulating environment, and voluntary exercise can rescue this deficit. We hypothesized that exercise alone is sufficient to rescue the cognitive deficit associated with perinatal anesthesia. METHODS:Postnatal day 7 male rats (P7) underwent isoflurane (Iso) or sham exposure and were subsequently weaned at P21. They were then singly housed in a cage with a running wheel or a fixed wheel. After 3 weeks of exercise, animals underwent behavioral testing for spatial and recognition memory assessments. Animals were killed at various time points to accomplish either bromodeoxyuridine (BrdU) labeling or quantitative real-time polymerase chain reaction (qRT-PCR) to quantify brain-derived neurotrophic factor (BDNF) messenger ribonucleic acid (mRNA) levels. RESULTS:Postweaning voluntary exercise rescued the long-term spatial memory deficit associated with perinatal Iso exposure. Iso-sedentary animals did not discriminate the goal quadrant, spending no more time than chance during the Barnes maze probe trial (1-sample t test, P = .524) while all other groups did (1-sample t test, PIso-exercise = .033; Pcontrol [Con]-sedentary = .004). We did not find a deficit in recognition memory tasks after Iso exposure as we observed previously. BrdU incorporation in the adult hippocampus of Iso-sedentary animals was decreased compared to sedentary controls (Tukey P = .005). Exercise prevented this decrease, with Iso-exercise animals having more proliferation than Iso-sedentary (Tukey P < .001). There was no effect of exercise or Iso on BDNF mRNA in either the cortex or hippocampus (cortex: FExercise[1,32] = 0.236, P = .631; FIso [1,32] = 0.038, P = .847; FInteraction [1,32] = 1.543, P = .223; and hippocampus: FExercise[1,33] = 1.186, P = .284; FIso [1,33] = 1.46, P = .236; FInteraction[1,33] = 1.78, P = .191). CONCLUSIONS:Exercise restores BrdU incorporation and rescues a spatial memory deficit after early life anesthesia exposure. This demonstrates sufficiency of exercise alone in the context of environmental enrichment to recover a behavioral phenotype after a perinatal insult.

Project description:BACKGROUND:A growing body of epidemiological literature indicates that particulate matter (PM) air pollution exposure is associated with elevated Alzheimer's disease (AD) risk and may exacerbate AD-related cognitive decline. Of concern is exposure to the ultrafine PM (UFP) fraction (≤100 nm), which deposits efficiently throughout the respiratory tract, has higher rates of translocation to secondary organs, like brain, and may induce inflammatory changes. We, therefore, hypothesize that exposure to UFPs will exacerbate cognitive deficits in a mouse model of AD. The present study assessed alterations in learning and memory behaviors in aged (12.5 months) male 3xTgAD and non-transgenic mice following a 2-week exposure (4-h/day, 4 days/week) to concentrated ambient UFPs using the Harvard ultrafine concentrated ambient particle system (HUCAPS) or filtered air. Beginning one month following exposure, locomotor activity, spatial learning and memory, short-term recognition memory, appetitive motivation, and olfactory discrimination were assessed. RESULTS:No effects on locomotor activity were found following HUCAPS exposure (number concentration, 1 × 104-4.7 × 105 particles/cm3; mass concentration, 29-132 μg/m3). HUCAPS-exposed mice, independent of AD background, showed a significantly decreased spatial learning, mediated through reference memory deficits, as well as short-term memory deficits in novel object recognition testing. AD mice displayed diminished spatial working memory, potentially a result of olfactory deficits, and short-term memory. AD background modulated HUCAPS-induced changes on appetitive motivation and olfactory discrimination, specifically enhancing olfactory discrimination in NTg mice. Modeling variation in appetitive motivation as a covariate in spatial learning and memory, however, did not support the conclusion that differences in motivation significantly underlie changes in spatial learning and memory. CONCLUSIONS:A short-term inhalation exposure of aged mice to ambient UFPs at human-relevant concentrations resulted in protracted (testing spanning 1-6.5 months post-exposure) adverse effects on multiple memory domains (reference and short-term memory) independent of AD background. Impairments in learning and memory were present when accounting for potential covariates like motivational changes and locomotor activity. These results highlight the need for further research into the potential mechanisms underlying the cognitive effects of UFP exposure in adulthood.

Project description:Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder, with onset in childhood and a considerable likelihood to persist into adulthood. Our previous work has identified that across adults and adolescents with ADHD, gray matter volume (GMV) alteration in the frontal cortex was consistently associated with working memory underperformance, and GMV alteration in the cerebellum was associated with inattention. Recent knowledge regarding ADHD genetic risk loci makes it feasible to investigate genomic factors underlying these persistent GMV alterations, potentially illuminating the pathology of ADHD persistence. Based on this, we applied a sparsity-constrained multivariate data fusion approach, sparse parallel independent component analysis, to GMV variations in the frontal and cerebellum regions and candidate risk single nucleotide polymorphisms (SNPs) data from 341 unrelated adult participants, including 167 individuals with ADHD, 47 unaffected siblings, and 127 healthy controls. We identified one SNP component significantly associated with one GMV component in superior/middle frontal regions and replicated this association in 317 adolescents from ADHD families. The association was stronger in individuals with ADHD than in controls, and stronger in adults and older adolescents than in younger ones. The SNP component highlights 93 SNPs in long non-coding RNAs mainly in chromosome 5 and 21 protein-coding genes that are significantly enriched in human neuron cells. Eighteen identified SNPs have regulation effects on gene expression, transcript expression, isoform percentage, or methylation level in frontal regions. Identified genes highlight MEF2C, CADM2, and CADPS2, which are relevant for modulating neuronal substrates underlying high-level cognition in ADHD, and their causality effects on ADHD persistence await further investigations. Overall, through a multivariate analysis, we have revealed a genomic pattern underpinning the frontal gray matter variation related to working memory deficit in ADHD.

Dataset Information

Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations.

Publications

Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets