TY - JOUR T1 - Targeting extracellular cyclophilin A reduces neuroinflammation and extends survival in a mouse model of amyotrophic lateral sclerosis JF - The Journal of Neuroscience JO - J. Neurosci. DO - 10.1523/JNEUROSCI.2462-16.2016 SP - 2462-16 AU - Laura Pasetto AU - Silvia Pozzi AU - Mariachiara Castelnovo AU - Manuela Basso AU - Alvaro G. Estevez AU - Stefano Fumagalli AU - Maria Grazia De Simoni AU - Valeria Castellaneta AU - Paolo Bigini AU - Elena Restelli AU - Roberto Chiesa AU - Francesca Trojsi AU - Maria Rosaria Monsurrò AU - Leonardo Callea AU - Miroslav Malešević AU - Gunter Fischer AU - Mattia Freschi AU - Massimo Tortarolo AU - Caterina Bendotti AU - Valentina Bonetto Y1 - 2016/12/23 UR - http://www.jneurosci.org/content/early/2017/01/11/JNEUROSCI.2462-16.2016.abstract N2 - Neuroinflammation is a major hallmark of amyotrophic lateral sclerosis (ALS), which is currently untreatable. Several anti-inflammatory compounds have been evaluated in patients and animal models of ALS, but have been proved disappointing, in part because effective targets have not yet been identified. Cyclophilin A (PPIA) as a foldase is beneficial intracellularly, but extracellularly has detrimental functions. We found that extracellular PPIA is a mediator of neuroinflammation in ALS. It is a major inducer of matrix metalloproteinase 9 and is selectively toxic for motor neurons. High levels of PPIA were found in cerebrospinal fluid of SOD1G93A mice and rats, and sporadic ALS patients, suggesting that our findings may be relevant for familial and sporadic cases. A specific inhibitor of extracellular PPIA, MM218, given at symptom onset, rescued motor neurons and extended survival in the SOD1G93A mouse model of familial ALS by 11 days. The treatment resulted in the polarization of glia toward a pro-healing phenotype associated with reduced NF-κB activation, pro-inflammatory markers, endoplasmic reticulum stress and insoluble phosphorylated TDP-43. Our results indicates that extracellular PPIA is a promising druggable target for ALS and support further studies to develop a therapy to arrest or slow the progression of the disease in patients.SIGNIFICANCE STATEMENTWe provide evidence that extracellular PPIA is a mediator of the neuroinflammatory reaction in ALS and is toxic for motor neurons. Supporting this, a specific extracellular PPIA inhibitor reduced neuroinflammation, rescued motor neurons and extended survival in the SOD1G93A mouse model of familial ALS. Our findings suggest selective pharmacological inhibition of extracellular PPIA as a novel therapeutic strategy not only for SOD1-linked, but possibly also for sporadic ALS. This approach aims at tackling the neuroinflammatory reaction that is a major hallmark of ALS. However, given the complexity of the disease, a combination of therapeutic approaches may be necessary. ER -