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Gianenrico Senna,1,2 Maria Aliani,3 Elena Altieri,4 Pietro Bracciale,5 Luisa Brussino,6 Maria Filomena Caiaffa,7 Paolo Cameli,8 Giorgio Walter Canonica,9,10 Cristiano Caruso,11 Maria D’Amato,12 Fausto De Michele,13 Stefano Del Giacco,14 Fabiano Di Marco,15 Francesco Menzella,16 Girolamo Pelaia,17 Paola Rogliani,18,19 Micaela Romagnoli,20 Pietro Schino,21 Jan Walter Schroeder,22 Alessandra Vultaggio,23 Sara Rizzoli,24 Alessandro Zullo,24 Silvia Boarino,25 Marilena Palmisano,26 Alessandra Rossi,26 Gianfranco Vitiello,26 Stefano Centanni27 1Department of Medicine, University of Verona, Verona, Italy; 2Allergy Unit and Asthma Center, Verona University Hospital, Verona, Italy; 3UO Pneumologia e Pneumologia Riabilitativa, ICS Maugeri, IRCCS Bari, Bari, Italy; 4Reparto di Pneumologia, P.O., Garbagnate Milanese, Italy; 5Reparto di Pneumologia, Ospedale Ostuni, Ostuni, BR, Italy; 6Dipartimento di Scienze Mediche, SSDDU Allergologia e Immunologia Clinica, Università degli Studi di Torino, AO Ordine Mauriziano Umberto I, Torino, Italy; 7Cattedra e Scuola di Allergologia e Immunologia Clinica, Dipartimento di Scienze Mediche, Università di Foggia, Foggia, Italy; 8Respiratory Diseases and Lung Transplantation, Department of Medical and Surgical Sciences & Neurosciences, Siena University Hospital, Siena, Italy; 9Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, MI, Italy; 10Personalized Medicine Center: Asthma and Allergology, Humanitas Research Hospital, Rozzano, MI, Italy; 11Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico A. Gemelli, IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy; 12UOSD Malattie Respiratorie “Federico II”, Ospedale Monaldi, AO Dei Colli, Napoli, Italy; 13UOC Pneumologia e Fisiopatologia Respiratoria, AORN A. Cardarelli, Napoli, Italy; 14Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; 15Department of Health Sciences, Università Degli Studi Di Milano, Pneumologia, ASST Papa Giovanni XXIII, Bergamo, Italy; 16UOC Pneumologia, Ospedale “S. Valentino”, AULSS 2 Marca Trevigiana, Montebelluna, TV, Italy; 17Dipartimento di Scienze della Salute, Università Magna Graecia, Catanzaro, Italy; 18Division of Respiratory Medicine, University Hospital “Tor Vergata”, Roma, Italy; 19Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome “Tor Vergata”, Roma, Italy; 20UOC Pneumologia, ULSS 2 Marca Trevigiana, Treviso, Italy; 21Fisiopatologia Respiratoria, Ospedale Generale Regionale, Ente Ecclesiastico “F. Miulli”, Acquaviva delle Fonti, BA, Italy; 22Allergy and Clinical Immunology, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy; 23Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Firenze, Firenze, Italy; 24Medineos Observational Research - An IQVIA Company, Modena, Italy; 25Medical Evidence R&I, AstraZeneca, Milano, Italy; 26Medical Affairs R&I, AstraZeneca, Milano, Italy; 27Respiratory Unit, ASST Santi Paolo e Carlo, Department of Health Sciences, Università degli Studi di Milano, Milano, ItalyCorrespondence: Marilena Palmisano, Medical Affairs R&I, AstraZeneca, Milano, Italy, Email marilena.palmisano@astrazeneca.comPurpose: Benralizumab effectively reduces severe eosinophilic asthma (SEA) exacerbations in patients with a wide range of baseline blood eosinophil count (BEC). Patients included in real-world studies are often characterized by high mean/median BEC, while patients with BEC close to 300 cells/mm3 are poorly represented. This post hoc analysis from the Italian study ANANKE aims to define the clinical features and corroborate the efficacy of benralizumab in real world in the BEC 300– 450 cells/mm3 subset of patients.Patients and Methods: Post hoc analysis of the Italian, multicenter, observational, retrospective real-life study ANANKE (NCT04272463). Baseline clinical and laboratory characteristics were collected in the 12 months prior to benralizumab treatment and presented for a BEC 300– 450 cells/mm3 subgroup of patients. Change over time of BEC, annualized exacerbation rate (AER), asthma control (ACT), lung function and oral corticosteroid (OCS) use at 16, 24 and 48 weeks after benralizumab introduction were collected.Results: A total of 164 patients were analyzed, 34 of whom with a BEC of 300– 450 cells/mm3. This subgroup was more likely to be female (64.7%), with lower rates of severe exacerbations at baseline when compared to the total population (0.69 vs 1.01). After 48 weeks of benralizumab treatment, the BEC 300– 450 subset showed similar reductions in AER (− 94.8% vs − 92.2%) and OCS use (median dose reduction of 100% in both groups), as well as improvement in ACT score (median scores 22.5 vs 22) and lung function (pre-BD FEV1: +200 mL vs +300 mL) when compared to the total population. No discontinuations for safety reasons were registered.Conclusion: At baseline, apart from lower severe exacerbation rate, the BEC 300– 450 cells/mm3 subset of patients is comparable to the total population prescribed with benralizumab. In this real-life study, benralizumab is as effective in BEC 300– 450 patients as in the total population.Keywords: severe eosinophilic asthma, blood eosinophil count, benralizumab, observational, real-world evidence, real-life

Delia Colombo,1 Emanuela Zagni,1 Mihaela Nica,1 Sara Rizzoli,2 Alessandra Ori,2 Gilberto Bellia1 1Patient Access, Novartis Farma S.p.A., Origgio, Varese, 2MediNeos Observational Research, Modena, Italy Background: MetaGeM is a wide gender-medicine project comprising post hoc and meta-analyses by gender of clinical outcomes, therapeutic approaches, and safety data from previously conducted observational studies to explore possible gender differences in real-life clinical settings. We report the results of the safety meta-analysis of seven MetaGeM studies, evaluating gender differences in adverse event (AE) incidence and severity. Methods: Data were collected between February 2002 and July 2013. Male and female patients were compared for the main safety variables, using Student’s t-test, χ² test, or Fisher’s exact test as appropriate. As supportive analysis, a logistic regression model was estimated to evaluate associations between gender and outcome. Results: In total, 4,870 patients (46% females, 54% males) were included in the analysis; age was higher for females (mean ± standard deviation 61.2±18.3 years) than males (56.3±16.6 years). Overall, 264 AEs were reported (59.1% in males). There were no significant gender differences in the percentage of patients with at least one AE: 3.0% for females versus 3.9% for males, χ² test P>0.05. According to the logistic regression model results, no association between gender and AEs occurrence seems to exist. A statistically significant gender difference in the percentage of drug-related AEs emerged (37.6% in females vs 20.8% in males, χ² P=0.0039). Slightly significantly more AEs in females were addressed with treatment compared with males (78.1% vs 66.7%, χ² P=0.0485). Total serious AEs (SAEs) were 47 (72% in males). The frequency of patients with ≥1 SAE was 0.6% in females versus 1.2% in males (χ² test P=0.0246). Conclusion: This safety analysis on a large sample of almost 5,000 patients with different diseases and treated with a wide range of different drugs provides a useful overview on possible gender differences in drug tolerability, which may be helpful in more accurately designing future clinical trials from a gender-specific perspective. Keywords: gender, drugs, safety, adverse events, meta-analysis

Delia Colombo,1 Gilberto Bellia,1 Donatella Vassellatti,1 Emanuela Zagni,1 Simona Sgarbi,2 Sara Rizzoli21Novartis Farma, Origgio, 2MediData, Modena, ltaly Abstract: Only recently has medical research begun to understand the importance of taking sex into account, recognizing that symptoms and responses to medical treatment may be very different between males and females. However, the analyses provided by the pharmaceutical industry to regulatory authorities often do not present safety and efficacy data by sex. Novartis has started a gender-medicine project called MetaGeM, which includes nine observational studies sponsored by Novartis Farma, Italy; conducted in Italy between 2002 and 2013 in a range of different clinical areas. The MetaGeM project aims to analyze and describe by means of post hoc analyses and meta-analyses, clinical outcomes, therapeutic approaches, and safety data of these studies, by sex: PSYCHAE; GENDER ATTENTION in psoriasis; Synergy in psoriatic arthritis; ICEBERG in HBsAg carriers; SURF and CETRA in liver- and renal transplanted patients, respectively; DEEP in Parkinson's disease; and EVOLUTION and AXEPT in Alzheimer's disease. The present paper describes the methodology of the MetaGeM project.Keywords: gender-medicine, MetaGeM project, methodology

Background: FIBRONET was an observational, multicentre, prospective cohort study investigating the baseline characteristics, clinical course of disease and use of antifibrotic treatment in Italian patients with idiopathic pulmonary fibrosis (IPF).Methods: Patients aged ≥ 40 years diagnosed with IPF within the previous 3 months at 20 Italian centres were consecutively enrolled and followed up for 12 months, with evaluations at 3, 6, 9 and 12 months. The primary objective was to describe the clinical course of IPF over 12 months of follow-up, including changes in lung function measured by % predicted forced vital capacity (FVC% predicted).Results: 209 patients (82.3% male, mean age 69.54 ± 7.43 years) were enrolled. Mean FVC% predicted was relatively preserved at baseline (80.01%). The mean time between IPF diagnosis and initiation of antifibrotic therapy was 6.38 weeks; 72.3% of patients received antifibrotic therapy within the first 3 months of follow-up, and 83.9% within 12 months of follow-up. Mean FVC% predicted was 80.0% at baseline and 82.2% at 12 months, and 47.4% of patients remained stable (i.e. had no disease progression) in terms of FVC% predicted during the study.Conclusions: FIBRONET is the first prospective, real-life, observational study of patients with IPF in Italy. The short time between diagnosis and initiation of antifibrotic therapy, and the stable lung function between baseline and 12 months, suggest that early diagnosis and prompt initiation of antifibrotic therapy may preserve lung function in patients with IPF.Trial Registration: NCT02803580. [ABSTRACT FROM AUTHOR]

Purpose: Benralizumab effectively reduces severe eosinophilic asthma (SEA) exacerbations in patients with a wide range of baseline blood eosinophil count (BEC). Patients included in real-world studies are often characterized by high mean/median BEC, while patients with BEC close to 300 cells/mm 3 are poorly represented. This post hoc analysis from the Italian study ANANKE aims to define the clinical features and corroborate the efficacy of benralizumab in real world in the BEC 300-450 cells/mm 3 subset of patients., Patients and Methods: Post hoc analysis of the Italian, multicenter, observational, retrospective real-life study ANANKE (NCT04272463). Baseline clinical and laboratory characteristics were collected in the 12 months prior to benralizumab treatment and presented for a BEC 300-450 cells/mm 3 subgroup of patients. Change over time of BEC, annualized exacerbation rate (AER), asthma control (ACT), lung function and oral corticosteroid (OCS) use at 16, 24 and 48 weeks after benralizumab introduction were collected., Results: A total of 164 patients were analyzed, 34 of whom with a BEC of 300-450 cells/mm 3 . This subgroup was more likely to be female (64.7%), with lower rates of severe exacerbations at baseline when compared to the total population (0.69 vs 1.01). After 48 weeks of benralizumab treatment, the BEC 300-450 subset showed similar reductions in AER (-94.8% vs -92.2%) and OCS use (median dose reduction of 100% in both groups), as well as improvement in ACT score (median scores 22.5 vs 22) and lung function (pre-BD FEV 1 : +200 mL vs +300 mL) when compared to the total population. No discontinuations for safety reasons were registered., Conclusion: At baseline, apart from lower severe exacerbation rate, the BEC 300-450 cells/mm 3 subset of patients is comparable to the total population prescribed with benralizumab. In this real-life study, benralizumab is as effective in BEC 300-450 patients as in the total population., Competing Interests: GS has nothing to declare; MA has nothing to declare; EA has nothing to declare; PB has nothing to declare; LB has nothing to declare; MFC has nothing to declare; PC reports having received in the last 3 years research grants and fees as speaker from AstraZeneca-MedImmune, Guidotti-Malesci and GlaxoSmithKline; GWC reports having received in the last 3 years research grants as well as lecture or advisory board fees from A. Menarini, Allergy – Therapeutics, AstraZeneca-MedImmune, Boehringer Ingelheim, Chiesi, Faes, Genentech, Guidotti-Malesci, GlaxoSmithKline, HAL Allergy, Novartis, Sanofi-Aventis, Sanofi-Genzyme/Regeneron, Stallergenes-Greer, Thermo Fisher, Valeas, Vifor Pharma; CC has nothing to declare; MDA has nothing to declare; FDMa has received lectures fees at national and international meetings and consultancy fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Dompé, Guidotti/Malesci, GlaxoSmithKline, Menarini, Novartis, and Zambon; SDG received grants and/or personal fees from AstraZeneca, Chiesi, Glaxo Smith Kline, Menarini, Novartis, Sanofi; FDMi has nothing to declare; FM declares research funding as Principal investigator by AstraZeneca, Chiesi Farmaceutici, Novartis, Sanofi; fees as speaker/lecturer by AstraZeneca, Chiesi Farmaceutici, GlaxoSmithKline, Novartis, Sanofi; GP has received lecture fees and consultancy fees from AlfaSigma, AstraZeneca, Chiesi, GlaxoSmithKline, Guidotti-Malesci, Menarini, Mundipharma, Novartis, Sanofi, Zambon; PR has participated as a lecturer, speaker, and advisor in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, Biofutura, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Menarini Group, Mundipharma, and Novartis, her department has received funding from Almirall, Boehringer Ingelheim, Chiesi, Novartis, and Zambon; MR declares grants and personal fees from Boehringer Ingelheim, Roche, AstraZeneca, Novartis, Chiesi, GSK, Menarini, Guidotti, AlfaSigma, Zambon; PS has nothing to declare; JWS has nothing to declare; AV participated as a lecturer/speaker in scientific meetings under the sponsorship of AstraZeneca, Chiesi, GlaxoSmithKline, Novartis; SR and AZ are employees of Medineos Observational Research – an IQVIA company, Modena Italy contracted by AstraZeneca, Italy; SB, MP and AR are AstraZeneca employees; GV was an AstraZeneca employee at the time of manuscript preparation; SC declares grants and/or personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Glaxo Smith Kline, Guidotti, Menarini, Novartis, Valeas., (© 2022 Senna et al.)

Background: Severe asthma is a heterogeneous inflammatory disease driven by eosinophilic inflammation in the majority of cases. Despite biologic therapy patients may still be sub-optimally controlled, and the choice of the best biologic is a matter of debate. Indeed, switching between biologics is common, but no official guidelines are available and real-world data are limited., Materials and Methods: In this post hoc analysis of the Italian, multi-center, observational, retrospective study, ANANKE. Patients with severe eosinophilic asthma treated with benralizumab were divided in two groups based on history of previous biologic therapy (biologic-experienced [suboptimal response] vs naïve). Baseline clinical and laboratory characteristics were collected in the 12 months prior to benralizumab treatment. Change over time in blood eosinophils, annualized exacerbation rate (AER), asthma control (ACT), lung function and oral corticosteroid (OCS) use following benralizumab initiation were collected in the two groups., Results: A total of 147 biologic-naïve and 58 biologic-experienced (34 omalizumab, 19 mepolizumab, and 5 omalizumab-mepolizumab) patients were enrolled. Biologic-experienced patients were more likely to be atopic and have a higher AER despite more frequent OCS use. Similar reductions in AER (>90% in both groups), OCS use (≥49% reduction in dosage and ≥41% able to eliminate OCS), ACT improvement (≥7 points gained in 48 weeks) and lung function (≥300 mL of FEV 1 improvement in 48 weeks) were observed after benralizumab introduction within the two groups. There were no registered discontinuations of benralizumab for safety reasons., Conclusion: In this post hoc analysis, patients who were switched to benralizumab because of suboptimal control with a previous biologic therapy were more likely to be atopic and more often treated with omalizumab. Benralizumab is effective in both naïve patients and those previously treated with a biologic., Competing Interests: FM declares research fundings as Principal Investigator by AstraZeneca, Chiesi Farmaceutici, Novartis, Sanofi; fees as speaker/lecturer by AstraZeneca, Chiesi Farmaceutici, GlaxoSmithKline, Novartis, Sanofi. SC declares grants and/or personal fees from AstraZeneca, Boheringer Ingelheim, Chiesi, Glaxo Smith Kline, Guidotti, Menarini, Novartis, Valeas. SD received grants and/or personal fees from AstraZeneca, Chiesi, Glaxo Smith Kline, Menarini, Novartis. FDi has received lectures fees at national and international meetings and consultancy fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Dompe, Guidotti/Malesci, GlaxoSmithKline, Menarini, Novartis, and Zambon. GP has received lecture fees and consultancy fees from Alfasigma, AstraZeneca, Chiesi, GlaxoSmithKline, Guidotti-Malesci, Menarini, Mundipharma, Novartis, Sanofi, and Zambon. PR has participated as a lecturer, speaker, and advisor in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, Biofutura, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Menarini Group, Mundipharma, and Novartis, her department has received funding from Almirall, Boehringer Ingelheim, Chiesi, Novartis, and Zambon. MR declares grants and personal fees from Boehringer Ingelheim, Roche, AstraZeneca, Novartis, Chiesi, GSK, Menarini, Guidotti, AlfaSigma, and Zambon. AV received payment for lectures and consultant arrangements from Novartis, GlaxoSmithKline, Teva, and AstraZeneca. GC has received grant/research support from Boehringer Ingelheim, ALK, and Stallergenes, and honoraria or consultation fees from Menarini, GSK, Sanofi, Teva, Hal, AstraZeneca, and Novartis. AZ and SR were employed by MediNeos Observational Research – an IQVIA company. SB and GV were employed by AstraZeneca SpA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Caruso, Cameli, Altieri, Aliani, Bracciale, Brussino, Caiaffa, Canonica, Centanni, D’Amato, Del Giacco, De Michele, Pastorello, Pelaia, Rogliani, Romagnoli, Schino, Caminati, Vultaggio, Zullo, Rizzoli, Boarino, Vitiello, Menzella and Di Marco.)

Background: Phenotypic features and outcome differences between sexes have been reported in psoriatic arthritis (PsA). However, little is known about sex differences in effectiveness of biologics in clinical practice. Methods: Post hoc gender analysis of the CHRONOS, a multicenter, noninterventional, retroprospective Italian real-world study assessing 6-month and 1-year effectiveness of biologics for PsA. Results: Eligible patients were 399, 43.1% men. Sociodemographic characteristics, type of arthritis, baseline Disease Activity Score 28 joints (DAS28), and duration of biologic treatment were rather homogeneous. More men were overweight/obese and naive to biologics. The most frequently used biologics were TNF-inhibitors and secukinumab in both sexes. DAS28 responders were 72.7% (women) and 70.5% (men) at 6 months, and 68.0% in both sexes at 1 year. American College of Rheumatology (ACR) response showed a trend for men versus women to achieve more frequently ACR50 (32.6% vs. 26.5% at 6 months; 34.9% vs. 20.0% at 1 year) and ACR70 (22.3% vs. 12.4% at 6 months and 25.0% vs. 13.0% at 1 year). Global satisfaction with treatment at enrollment and after 6 months was slightly higher among men [mean (standard deviation) Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) score: 68.6 (18.6) and 69.9 (18.2), respectively] than women [65.3 (18.2), 66.2 (18.5)]. Conclusions: Overall response to biologics for PsA was rather favorable. With similar baseline disease severity, men appear to have a somewhat earlier and better response with higher treatment satisfaction., Competing Interests: D.C. was a part-time employee of Novartis Farma Italy when the study was conducted. F.I. received speaker/consultation fees from AbVie, Roche, MSD, UCB, Lily, Jansen, Sanofi, Pfizer, and Novartis. F.C. received speaker fees from Abbvie, Lilly, BMS, Galapagos, and Pfizer. S.R. is an employee of MediNeos Observational Research (Modena, Italy), hired by Novartis Farma Italy, responsible for the design and conduction of the CHRONOS study, as well as scientific support, clinical operations, data management, and statistical analysis. B.R. is an employee of MediNeos Observational Research (Modena, Italy), hired by Novartis Farma Italy, responsible for the design and conduction of the CHRONOS study, as well as scientific support, clinical operations, data management, and statistical analysis. M.F., R.O., and E.Z. are employees of Novartis Farma Italy. No further CoI were declared., (© Delia Colombo et al., 2021; Published by Mary Ann Liebert, Inc.)

In adult cornu ammonis hippocampi, erythropoietin (EPO) expression drives the differentiation of new neurons, independent of DNA synthesis, and increases dendritic spine density. This substantial brain hardware upgrade is part of a regulatory circle: during motor-cognitive challenge, neurons experience "functional" hypoxia, triggering neuronal EPO production, which in turn promotes improved performance. Here, we show an unexpected involvement of resident microglia. During EPO upregulation and stimulated neurodifferentiation, either by functional or inspiratory hypoxia, microglia numbers decrease. Treating mice with recombinant human (rh)EPO or exposure to hypoxia recapitulates these changes and reveals the involvement of neuronally expressed IL-34 and microglial CSF1R. Surprisingly, EPO affects microglia in phases, initially by inducing apoptosis, later by reducing proliferation, and overall dampens microglia activity and metabolism, as verified by selective genetic targeting of either the microglial or pyramidal neuronal EPO receptor. We suggest that during accelerating neuronal differentiation, EPO acts as regulator of the CSF1R-dependent microglia., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: This paper is aimed to (i) develop an innovative classification of COPD, multi-dimensional phenotype, based on a multidimensional assessment; (ii) describe the identified multi-dimensional phenotypes., Methods: An exploratory factor analysis to identify the main classificatory variables and, then, a cluster analysis based on these variables were run to classify the COPD-diagnosed 514 patients enrolled in the STORICO (trial registration number: NCT03105999) study into multi-dimensional phenotypes., Results: The circadian rhythm of symptoms and health-related quality of life, but neither comorbidity nor respiratory function, qualified as primary classificatory variables. Five multidimensional phenotypes were identified: the MILD COPD characterized by no night-time symptoms and the best health status in terms of quality of life, quality of sleep, level of depression and anxiety, the MILD EMPHYSEMATOUS with prevalent dyspnea in the early-morning and day-time, the SEVERE BRONCHITIC with nocturnal and diurnal cough and phlegm, the SEVERE EMPHYSEMATOUS with nocturnal and diurnal dyspnea and the SEVERE MIXED COPD distinguished by higher frequency of symptoms during 24h and worst quality of life, of sleep and highest levels of depression and anxiety., Conclusions: Our results showed that properly collected respiratory symptoms play a primary classificatory role of COPD patients. The longitudinal observation will disclose the discriminative and prognostic potential of the proposed multidimensional phenotype., Trial Registration: Trial registration number: NCT03105999, date of registration: 10th April 2017., Competing Interests: B.F. reports grants and personal fees from ASTRAZENECA (https://www.astrazeneca.com/), grants and personal fees from BAYER (https://www.bayer.com/), personal fees from CHIESI (https://www.chiesi.com/), personal fees from GSK (https://it.gsk.com/), personal fees from GUIDOTTI (https://www.labguidotti.it/), grants and personal fees from GRIFOLS (https://www.grifols.com/en/home), grants from INSMED (https://www.insmed.com/), 408 personal fees from MENARINI (https://www.menarini.it), personal fees from NOVARTIS (https://www.novartis.com/), grants and personal fees from PFIZER (https://www.pfizer.com/), personal fees from TEVA (https://www.tevapharm.com/), personal fees from ZAMBON (https://www.zambon.com/it), outside the submitted work. R.S. and S.L. are employees of Medineos Observational Research (http://www.medineos.com/) and received salary from this company. This does not alter authors adherence to PLOS ONE policies on sharing data and materials. The other authors declare that they have no competing interests.

Alpha-synuclein (aSyn) accumulates in intracellular inclusions in synucleinopathies, but the molecular mechanisms leading to disease are unclear. We identify the 10 kDa heat shock protein (HSP10) as a mediator of aSyn-induced mitochondrial impairments in striatal synaptosomes. We find an age-associated increase in the cytosolic levels of HSP10, and a concomitant decrease in the mitochondrial levels, in aSyn transgenic mice. The levels of superoxide dismutase 2, a client of the HSP10/HSP60 folding complex, and synaptosomal spare respiratory capacity are also reduced. Overexpression of HSP10 ameliorates aSyn-associated mitochondrial dysfunction and delays aSyn pathology in vitro and in vivo. Altogether, our data indicate that increased levels of aSyn induce mitochondrial deficits, at least partially, by sequestering HSP10 in the cytosol and preventing it from acting in mitochondria. Importantly, these alterations manifest first at presynaptic terminals. Our study not only provides mechanistic insight into synucleinopathies but opens new avenues for targeting underlying cellular pathologies., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The insulin-like growth factor-1 receptor (IGF-1R) signaling is a key regulator of lifespan, growth, and development. While reduced IGF-1R signaling delays aging and Alzheimer's disease progression, whether and how it regulates information processing at central synapses remains elusive. Here, we show that presynaptic IGF-1Rs are basally active, regulating synaptic vesicle release and short-term plasticity in excitatory hippocampal neurons. Acute IGF-1R blockade or transient knockdown suppresses spike-evoked synaptic transmission and presynaptic cytosolic Ca(2+) transients, while promoting spontaneous transmission and resting Ca(2+) level. This dual effect on transmitter release is mediated by mitochondria that attenuate Ca(2+) buffering in the absence of spikes and decrease ATP production during spiking activity. We conclude that the mitochondria, activated by IGF-1R signaling, constitute a critical regulator of information processing in hippocampal neurons by maintaining evoked-to-spontaneous transmission ratio, while constraining synaptic facilitation at high frequencies. Excessive IGF-1R tone may contribute to hippocampal hyperactivity associated with Alzheimer's disease., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)