Fear circuit-based neurobehavioral signatures mirror resilience to chronic social stress in mouse.

Consistent evidence from human data points to successful threat-safety discrimination and responsiveness to extinction of fear memories as key characteristics of resilient individuals. To promote valid cross-species approaches for the identification of resilience mechanisms, we establish a translationally informed mouse model enabling the stratification of mice into three phenotypic subgroups following chronic social defeat stress, based on their individual ability for threat-safety discrimination and conditioned learning: the Discriminating-avoiders, characterized by successful social threat-safety discrimination and extinction of social aversive memories; the Indiscriminate-avoiders, showing aversive response generalization and resistance to extinction, in line with findings on susceptible individuals; and the Non-avoiders displaying impaired aversive conditioned learning. To explore the neurobiological mechanisms underlying the stratification, we perform transcriptome analysis within three key target regions of the fear circuitry. We identify subgroup-specific differentially expressed genes and gene networks underlying the behavioral phenotypes, i.e., the individual ability to show threat-safety discrimination and respond to extinction training. Our approach provides a translationally informed template with which to characterize the behavioral, molecular, and circuit bases of resilience in mice.

Meprin ß knockout reduces brain Aß levels and rescues learning and memory impairments in the APP/lon mouse model for Alzheimer's disease.

ß-Site amyloid precursor protein (APP) cleaving enzyme-1 (BACE1) is the major described ß-secretase to generate Aß peptides in Alzheimer's disease (AD). However, all therapeutic attempts to block BACE1 activity and to improve AD symptoms have so far failed. A potential candidate for alternative Aß peptides generation is the metalloproteinase meprin ß, which cleaves APP predominantly at alanine in p2 and in this study we can detect an increased meprin ß expression in AD brain. Here, we report the generation of the transgenic APP/lon mouse model of AD lacking the functional Mep1b gene (APP/lon × Mep1b-/-). We examined levels of canonical and truncated Aß species using urea-SDS-PAGE, ELISA and immunohistochemistry in brains of APP/lon mouse × Mep1b-/-. Additionally, we investigated the cognitive abilities of these mice during the Morris water maze task. Aß1-40 and 1-42 levels are reduced in APP/lon mice when meprin ß is absent. Immunohistochemical staining of mouse brain sections revealed that N-terminally truncated Aß2-x peptide deposition is decreased in APP/lon × Mep1b-/- mice. Importantly, loss of meprin ß improved cognitive abilities and rescued learning behavior impairments in APP/lon mice. These observations indicate an important role of meprin ß within the amyloidogenic pathway and Aß production in vivo.

IntelliPy: a GUI for analyzing IntelliCage data.

SUMMARY: The IntelliCage systems offer the possibility to conduct long-term behavioral experiments on mice in social groups without human intervention. Although this setup provides new findings, only about 150 studies with the IntelliCage system have been published in the last two decades, which is also caused by the challenging problems of processing and handling the large and heterogeneous amounts of captured data. This application note introduces the Python-GUI IntelliPy, especially designed for users not very experienced in using programming languages. IntelliPy allows users to quickly analyze the IntelliCage output in a user-friendly way, thus making the systems more accessible to a broader audience. AVAILABILITY AND IMPLEMENTATION: https://github.com/NiRuff/IntelliPy. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Dietary Wheat Amylase Trypsin Inhibitors Impact Alzheimer's Disease Pathology in 5xFAD Model Mice.

Wheat amylase trypsin inhibitors (ATIs) represent a common dietary protein component of gluten-containing cereals (wheat, rye, and barley). They act as toll-like receptor 4 ligands, and are largely resistant to intestinal proteases, eliciting a mild inflammatory response within the intestine after oral ingestion. Importantly, nutritional ATIs exacerbated inflammatory bowel disease and features of fatty liver disease and the metabolic syndrome in mice. For Alzheimer's disease (AD), both inflammation and altered insulin resistance are major contributing factors, impacting onset as well as progression of this devastating brain disorder in patients. In this study, we evaluated the impact of dietary ATIs on a well-known rodent model of AD (5xFAD). We assessed metabolic, behavioral, inflammatory, and microbial changes in mice consuming different dietary regimes with and without ATIs, consumed ad libitum for eight weeks. We demonstrate that ATIs, with or without a gluten matrix, had an impact on the metabolism and gut microbiota of 5xFAD mice, aggravating pathological hallmarks of AD. If these findings can be translated to patients, an ATI-depleted diet might offer an alternative therapeutic option for AD and warrants clinical intervention studies.

(Neg)Entropic Scenarios Affecting the Wicked Design Spaces of Knowledge Management Systems.

The envisioned embracing of thriving knowledge societies is increasingly compromised by threatening perceptions of information overload, attention poverty, opportunity divides, and career fears. This paper traces the roots of these symptoms back to causes of information entropy and structural holes, invisible private and undiscoverable public knowledge which characterize the sad state of our current knowledge management and creation practices. As part of an ongoing design science research and prototyping project, the article's (neg)entropic perspectives complement a succession of prior multi-disciplinary publications. Looking forward, it proposes a novel decentralized generative knowledge management approach that prioritizes the capacity development of autonomous individual knowledge workers not at the expense of traditional organizational knowledge management systems but as a viable means to foster their fruitful co-evolution. The article, thus, informs relevant stakeholders about the current unsustainable status quo inhibiting knowledge workers; it presents viable remedial options (as a prerequisite for creating the respective future generative Knowledge Management (KM) reality) to afford a sustainable solution with the generative potential to evolve into a prospective general-purpose technology.

Transnasal delivery of human A-beta peptides elicits impaired learning and memory performance in wild type mice.

BACKGROUND: Murine models of Alzheimer's disease (AD) are mainly based on overexpression of pathologic amyloid precursor protein and/or presenilins. Those genes resemble underlying cause of early onset type of AD while about 99 % of all human cases are to be characterized as sporadic, late onset. Appropriate animal models for this type of AD are still missing. We here investigated, if transnasal delivery of A-beta 42 peptides might serve to mimic pathological effects in mice. RESULTS: A-beta 42 peptides, used for the behavioral study, showed the expected dose-dependent toxicity in neur oblastoma cell line SH-SY5Y and were able to form higher molecular weight species in vitro. Upon delivery into nostrils of wild type mice, protein bands that might represent aggregation products of the exogenously applied human A-beta 42 were only observed in total brain homogenates from mice pre-treated with mannitol. By using TAMRA-labeled A-beta 42 peptides we demonstrated, that transport throughout the brain was achieved already 1 h after administration. FVB/N mice treated with A-beta 42 for 3 days were significantly impaired in the cue-retention condition of the fear conditioning task as compared to controls whereas A-beta-treated C57B6/J mice were impaired in the context condition. In the Morris water maze test, these mice also displayed a delayed learning performance, indicated by significantly longer time to find the platform. Those deficits were also seen for memory performance in the probe trial as measured by number of crossings of the former platform position and time spent in the goal quadrant. CONCLUSIONS: Existing AD mouse models are of genetic origin and need prolonged housing time before onset of pathology. Our short-term treatment induced learning and memory deficits via exogenous application of A-beta peptides comparable to those observed for the transgenic animals. With the transnasal A-beta 42 treatment we present an approach to investigate purely A-beta related changes suitable as a model for symptoms of Alzheimer's dementia (AD). Resulting behavioral deficits were indicative for familial type of Alzheimer's disease as well as for the late onset variant.

Chronic Administration of Δ9-Tetrahydrocannabinol Alters Brain Glucose Uptake and Improves Waiting Impulsivity in the Rat.

Introduction: Δ9-Tetrahydrocannabinol (THC) acts as an agonist at cannabinoid receptors. Its chronic intake affects many behaviors, including cognitive processes. The aims of this study in rats are to assess the chronic effects of THC on impulsivity and on regional brain glucose uptake. Materials and Methods: For the determination of "waiting impulsivity," a total of 20 male Lister Hooded rats were trained to perform a reaction time task, followed by a baseline test of impulsivity and baseline glucose uptake measurements with [18F]-fluoro-2-deoxy-D-glucose and positron emission tomography (PET). Then, 10 rats each received 3 mg/kg THC or vehicle injected intraperitoneally daily for 21 days. Subsequently, a second behavioral test and PET measurements were performed, and blood THC concentrations were determined. Analyses of variance of brain regions of the impulsivity network with the parameter "standardized uptake value" regarding glucose uptake and correlation analyses of the collected parameters were carried out. Discussion: After chronic THC treatment, decreased glucose uptake (p-values <0.05) was found in cingulate cortex, hippocampus, amygdala, thalamus, and cerebellar cortex, as compared with vehicle-treated rats. The number of correct no-go responses (increased waiting time) significantly increased (p<0.05) in THC-treated rats. Furthermore, correct no-go responses correlated positively and strongly with the THC blood concentrations (Spearman's ρ=0.79, p<0.01). Conclusion: These findings reflect a specific reduction in impulsive behavior after chronic THC treatment, showing a functionally relevant influence of THC on "waiting impulsivity" with reduced selective glucose uptake at the same time.

Social Threat-Safety Test Uncovers Psychosocial Stress-Related Phenotypes.

Social stress is a major cause of the development of mental disorders. To enhance the translational value of preclinical studies, social stress experience and its behavioral impact on mice should be comparable to humans. Chronic social defeat (CSD) utilizes a type of social stress involving physical attacks and sensory threats to induce mental dysfunctions resembling human affective disorders. To strengthen the psychosocial component of CSD, a 10-day CSD protocol was applied in which daily physical attacks are standardized to three 10 s episodes followed by a 24 h sensory phase. After the 10th sensory phase, the CSD protocol is followed by a refined behavioral assay called the social threat-safety test (STST). Post-stress behavioral assays need to determine how and to what extent the social stressor has influenced behavior. The STST allows chronically socially defeated male mice to interact with 2 novel male individuals (social targets): one social target from the attacking strain encountered during the CSD days and the other from a novel strain. Both are presented simultaneously in different compartments of a three-chambered test arena. The test enables a simultaneous assessment of social avoidance development to measure successful aversive conditioned learning and social threat-safety discrimination ability. The development of social avoidance towards both strains reflects a generalized aversive response and thus, a measurement of stress susceptibility. Meanwhile, the development of social avoidance towards only the attacking strain reflects threat-safety discrimination and thus, a measurement of stress resilience. Finally, the absence of social avoidance towards the attacking strain reflects impaired aversive conditioned learning. The protocol aims to refine the currently used mouse models of stress susceptibility/resilience by including translational criteria, specifically threat-safety discrimination and aversive response generalization, to categorize a single group of chronically socially defeated animals into resilient and susceptible subgroups, eventually advancing future translational approaches.

Neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) slows down Alzheimer's disease-like pathology in amyloid precursor protein-transgenic mice.

Pituitary adenylate cyclase-activating polypeptide (PACAP) has neuroprotective and neurotrophic properties and is a potent α-secretase activator. As PACAP peptides and their specific receptor PAC1 are localized in central nervous system areas affected by Alzheimer's disease (AD), this study aims to examine the role of the natural peptide PACAP as a valuable approach in AD therapy. We investigated the effect of PACAP in the brain of an AD transgenic mouse model. The long-term intranasal daily PACAP application stimulated the nonamyloidogenic processing of amyloid precursor protein (APP) and increased expression of the brain-derived neurotrophic factor and of the antiapoptotic Bcl-2 protein. In addition, it caused a strong reduction of the amyloid ß-peptide (Aß) transporter receptor for advanced glycation end products (RAGE) mRNA level. PACAP, by activation of the somatostatin-neprilysin cascade, also enhanced expression of the Aß-degrading enzyme neprilysin in the mouse brain. Furthermore, daily PAC1-receptor activation via PACAP resulted in an increased mRNA level of both the PAC1 receptor and its ligand PACAP. Our behavioral studies showed that long-term PACAP treatment of APP[V717I]-transgenic mice improved cognitive function in animals. Thus, nasal application of PACAP was effective, and our results indicate that PACAP could be of therapeutic value in treating AD.

Acitretin, an enhancer of alpha-secretase expression, crosses the blood-brain barrier and is not eliminated by P-glycoprotein.

BACKGROUND: ADAM10 (a disintegrin and metalloproteinase 10) has been demonstrated to act as the main physiological α-secretase. Enzymatic activity of the α-secretase on the one hand prevents the formation of toxic Aß peptides and on the other hand promotes the secretion of a neurotrophic and neuroprotective amyloid precursor protein fragment (APPs-α) by cleaving the amyloid precursor protein within its Aß sequence. Enhancement of ADAM10's gene expression may therefore present a valuable therapeutic approach for the treatment of Alzheimer's disease (AD), where Aß peptides are severely involved in the pathogenesis. OBJECTIVE: In cell culture and in a transgenic mouse model of AD, retinoids led to increased ADAM10 expression and activity. We therefore endeavor to develop a clinical application of synthetic retinoids such as acitretin in AD. METHODS: The effect of synthetic retinoids on ADAM10 gene expression was analyzed by reporter gene assays in human neuroblastoma cell line SH-SY5Y. Penetrance of acitretin into the murine brain was analyzed by high-performance liquid chromatography. P-glycoprotein (P-gp) double-knockout mice with a deficiency in both isoforms, mdr1a and 1b, were used to analyze a possible role of P-gp-dependent efflux on acitretin distribution. RESULTS: Acitretin and tamibarotene are both potent activators of ADAM10 promoter activity. Acitretin crosses the murine blood-brain barrier and its level in the mouse brain is not reduced by P-gp. CONCLUSION: Synthetic retinoids and especially acitretin seem to be ideal candidates to establish an ADAM10-based AD treatment, and therefore have already entered first clinical trials.

P-glycoprotein influence on the brain uptake of a 5-HT(2A) ligand: [(18)F]MH.MZ.

BACKGROUND/AIMS: The serotonergic system, especially the 5-HT(2A) receptor, is involved in various diseases and conditions. We have recently developed a new [(18)F]-5-HT(2A) receptor ligand using an analogue, MDL 100907, as a basis for molecular imaging with positron emission tomography. This tracer, [(18)F]MH.MZ, has been shown to be an adequate tool to visualize the 5-HT(2A) receptors in vivo. However, [(18)F]altanserin, similar in chemical structure, is a substrate of efflux transporters, such as P-glycoprotein (P-gp), of the blood-brain barrier, thus limiting its availability in the central nervous system. The aim of this study was to determine whether transport by P-gp influences the distribution ratio of [(18)F]MH.MZ in the frontal cortex. METHODS: The approach was based on P-gp knockout mice which were compared with wild-type mice under several conditions. In vivo pharmacokinetic and microPET investigations were carried out. RESULTS: All analyses showed that [(18)F]MH.MZ entered the brain and was sensitive to P-gp transport. In P-gp knockout mice, brain concentrations of MH.MZ were about 5-fold higher than in wild-type animals which is reflected by a 2-fold increase in standardized uptake values of [(18)F]MH.MZ in the frontal cortex of P-gp knockout mice. CONCLUSION: Our results give evidence for a functional role of transport mechanisms at the blood-brain barrier, specifically of P-gp, and its subregional distribution. Investigation of these mechanisms will benefit the development of more efficient radioligands and drugs for molecular imaging and pharmacotherapy of the mentally ill.

HPMA based amphiphilic copolymers mediate central nervous effects of domperidone.

In this study we give evidence that domperidone encapsulated into amphiphilic p(HPMA)-co-p(laurylmethacrylate) (LMA) copolymer aggregates is able to cross the blood-brain barrier, since it affected motor behaviour in animals, which is a sensitive measure for CNS actions. Carefully designed copolymers based on the clinically approved p(HPMA) were selected and synthesized by a combination of controlled radical polymerization and post-polymerization modification. The hydrodynamic radii (R(h) ) of amphiphilic p(HPMA)-co-p(LMA) alone and loaded with domperidone were determined by fluorescence correlation spectroscopy.

Individual baseline behavioral traits predict the resilience phenotype after chronic social defeat.

Chronic social defeat (CSD) has been widely used as a psychosocial stress model in mice, with the magnitude of CSD-induced social avoidance as the major behavioral hallmark of the resilient and susceptible groups. Despite significant progress in the study of the neurobiology of resilient and susceptible mice, the nature and ethological relevance of CSD-induced social avoidance and social approach, particularly measured using a CD1 mouse, needs conceptual clarification. Based on the findings of a recent study revealing substantial individuality in genetically homogeneous inbred mice, we investigated whether certain baseline individual characteristics of male C57BL/6J mice predict the resilient outcome after CSD. We focused on two well-studied individual traits that seem to have heritable underpinnings-approach to novelty and avoidance of harm, which are essential for the expression of the exploratory drive. Our results showed that the exploration levels and the approach to novelty and harm were different before and after CSD in resilient and susceptible mice. Before the stress, resilient mice had higher horizontal activity in a novel environment, shorter approach latencies, and higher exploration times for social and non-social targets than susceptible mice. However, susceptible mice performed better in the passive avoidance task than resilient mice as they were more successful in learning to avoid potential adversity by suppressing the spontaneous exploratory drive. Our findings challenge the validity of the current selection criteria for the susceptible and resilient groups and encourage comprehensive assessment of both baseline and stress-induced individual behavioral signatures of mice.

Acitretin reverses early functional network degradation in a mouse model of familial Alzheimer's disease.

Aberrant activity of local functional networks underlies memory and cognition deficits in Alzheimer's disease (AD). Hyperactivity was observed in microcircuits of mice AD-models showing plaques, and also recently in early stage AD mutants prior to amyloid deposition. However, early functional effects of AD on cortical microcircuits remain unresolved. Using two-photon calcium imaging, we found altered temporal distributions (burstiness) in the spontaneous activity of layer II/III visual cortex neurons, in a mouse model of familial Alzheimer's disease (5xFAD), before plaque formation. Graph theory (GT) measures revealed a distinct network topology of 5xFAD microcircuits, as compared to healthy controls, suggesting degradation of parameters related to network robustness. After treatment with acitretin, we observed a re-balancing of those network measures in 5xFAD mice; particularly in the mean degree distribution, related to network development and resilience, and post-treatment values resembled those of age-matched controls. Further, behavioral deficits, and the increase of excitatory synapse numbers in layer II/III were reversed after treatment. GT is widely applied for whole-brain network analysis in human neuroimaging, we here demonstrate the translational value of GT as a multi-level tool, to probe networks at different levels in order to assess treatments, explore mechanisms, and contribute to early diagnosis.

Chronic social defeat-induced social avoidance as a proxy of stress resilience in mice involves conditioned learning.

Chronic social defeat (CSD)-induced social avoidance is considered to model a feature of stress-related mental dysfunction, while its absence has been used as a proxy of resilience in rodents. However, knowledge on the mechanisms shaping CSD-induced individual outcomes remains fragmentary. Fear conditioning has been described as a suitable model in humans for better understanding the pathophysiology of stress related mental disorders. We sought to explore the extent to which conditioned learning is involved in CSD-induced social avoidance. In experiment 1 (social avoidance specificity), C57BL/6 J male mice underwent CSD followed by a modified social interaction test offering the simultaneous choice between an unknown mouse from the aggressor's strain or a mouse from a different strain and phenotypic characteristics. In experiment 2 (social avoidance extinction), CSD-extinction sessions involving only the sensory phase of CSD were conducted on one group of defeated mice whereas a second group only received handling, followed by social interaction test with a novel mouse from the aggressor's strain. Our results provide evidence that CSD-induced social avoidance does not generalize to other phenotypic characteristics than those of the aggressors and can be successfully reversed during extinction training. Taken together, our findings strongly point to the involvement of conditioned learning in shaping CSD-induced social avoidance, a finding that is of interest to future studies into the neurobiology of resilience.

Stress inoculation in mice induces global resilience.

Each year, more than half a billion people in the world are affected by stress-related health disorders. Consequently, there is an urgent need for new insights to guide interventions designed to increase stress resilience. Studies of humans and various animals have uncovered the process of stress inoculation, in which exposure to mild stressors enhances subsequent stress resilience. Here, we investigate whether stress inoculation-induced resilience in mice consistently occurs across a multiplicity of different stress contexts (tests). C57BL/6 J adult male mice were randomised either to stress inoculation training (n = 36) or to a non-inoculated, but handled control condition (n = 36). Thereafter, indications of coping and resilience were assessed during (i) acute social defeat in a context similar to that used for stress inoculation training, and (ii) fear conditioning and learned extinction in a novel context. Stress inoculation effects were also assessed during (iii) tail-suspension and (iv) open-field tests that each represent milder stressors. Stress-inoculated mice showed more active defence behaviour during acute social defeat, higher sociability before and after defeat, and greater indications of learned extinction of conditioned fear compared to non-inoculated control mice. Stress-inoculated mice also responded with diminished tail-suspension immobility and open-field defecation. Results suggest that stress inoculation protects against various stressors that differ in quality and relative intensity. Stress inoculation research in mice may serve as the basis for mechanistic studies of global resilience in humans.

Effect of a dominant-negative form of ADAM10 in a mouse model of Alzheimer's disease.

The alpha-secretase cleaves in the non-amyloidogenic pathway the amyloid-beta protein precursor (AbetaPP) within the region of the amyloid-beta peptides to prevent their formation and aggregation in the brain. Members of the ADAM family (a disintegrin and metalloprotease) are the main candidates for physiologically relevant alpha-secretases. We recently demonstrated that overexpression of ADAM10 in mice transgenic for human AbetaPP (ADAM10 x APP[V717I]) alleviated functional deficits related to Alzheimer's disease. To further demonstrate that this is due to the specific activity of alpha-secretase, we characterized mice overexpressing an inactive form of ADAM10 (ADAM10[E384A]; ADAM10-dn). Three lines of mice (controls (C57Bl/6 x FVB), APP[V717I[ transgenics and ADAM10-dn x APP[V717I] double-transgenics) were investigated with respect to learning and memory in the Morris water maze. Double-transgenic mice overexpressing ADAM10-dn behaved similar to APP[V717I] overexpressing mice. This provides further evidence that ADAM10 in vivo by its enzymatic activity is able to counteract cognitive deficits. Stimulation of alpha-secretase activity might thus be a suitable approach to study treatment strategies of Alzheimer's disease.

Rotarod impairment: catalepsy-like screening test for antipsychotic side effects.

Extrapyramidal motoric symptoms are casual side effects under antipsychotic medication. New generation antipsychotics are expected to have a reduced risk due to different receptor affinities. Here, haloperidol and the new generation antipsychotics, risperidone, amisulpride, and aripiprazole, were examined with both catalepsy test and rotarod performance test to screen for their usability in mice. Mice treated with haloperidol, risperidone, and aripiprazole showed dose and time-dependent impairment. Amisulpride-treated mice showed no signs of catalepsy. Catalepsy test and rotarod performance test were useful methods to detect side effects of both generation antipsychotics. Catalepsy test provided more specificity whereas the rotarod test provided higher degree of sensitivity to motor impairment including catalepsy.

Pharmacodynamic consequences of P-glycoprotein-dependent pharmacokinetics of risperidone and haloperidol in mice.

Efflux transporters, like P-glycoprotein (P-gp), may limit the access of drugs to the brain via the blood-brain barrier. The antipsychotic drug risperidone and its active metabolite 9-hydroxyrisperidone (paliperidone) are substrates of P-gp. Motor behavior of P-gp deficient mice (mdr1a/1b (-/-, -/-)) and wild type animals on a rotarod after acute doses of risperidone or haloperidol, a nonsubstrate of P-gp, were analysed aiming to show that P-gp substrate properties of an antipsychotic drug have functional consequences. Behavioral tests revealed dose-dependent effects of 0.3-3 mg/kg risperidone in wild type animals 0.5-12 h after i.p. injection of the drug. In knockout mice the 0.3 mg/kg dose of risperidone was as effective as the 3 mg/kg dose in wild type mice. A dose of 0.3 mg/kg haloperidol, however, exhibited similar pharmacodynamic effects in both genotypes. Brain concentrations of risperidone plus 9-hydroxyrisperidone were 10-fold higher in knockout than in wild type animals whereas brain concentrations of haloperidol did not differ between the two genotypes. P-gp-dependent brain distribution kinetics and behavioral effects of risperidone give evidence that the expression of P-gp has an impact on psychotropic drug actions when treating patients with drugs that are substrates of P-gp.

Identification of disulfiram as a secretase-modulating compound with beneficial effects on Alzheimer's disease hallmarks.

ADAM10 is a metalloproteinase acting on the amyloid precursor protein (APP) as an alpha-secretase in neurons. Its enzymatic activity results in secretion of a neuroprotective APP cleavage product (sAPP-alpha) and prevents formation of the amyloidogenic A-beta peptides, major hallmarks of Alzheimer's disease (AD). Elevated ADAM10 levels appeared to contribute to attenuation of A-beta-plaque formation and learning and memory deficits in AD mouse models. Therefore, it has been assumed that ADAM10 might represent a valuable target in AD therapy. Here we screened a FDA-approved drug library and identified disulfiram as a novel ADAM10 gene expression enhancer. Disulfiram increased ADAM10 production as well as sAPP-alpha in SH-SY5Y human neuronal cells and additionally prevented A-beta aggregation in an in vitro assay in a dose-dependent fashion. In addition, acute disulfiram treatment of Alzheimer model mice induced ADAM10 expression in peripheral blood cells, reduced plaque-burden in the dentate gyrus and ameliorated behavioral deficits. Alcohol-dependent patients are subjected to disulfiram-treatment to discourage alcohol-consumption. In such patients, enhancement of ADAM10 by disulfiram-treatment was demonstrated in peripheral blood cells. Our data suggest that disulfiram could be repurposed as an ADAM10 enhancer and AD therapeutic. However, efficacy and safety has to be analyzed in Alzheimer patients in the future.