1 Scientific RepoRts | 6:22605 | DOI: 10.1038/srep22605 www.nature.com/scientificreports Autologous transplantation of intestine-isolated glia cells improves neuropathology and restores cognitive deicits in β amyloid-induced neurodegeneration Giuseppe esposito 1,* , Giovanni sarnelli 2,* , elena Capoccia 1 , Carla Cirillo 3 , Marcella pesce 2 , Jie Lu 4 , Gaetano Calì 5 , Rosario Cuomo 2 & Luca steardo 1 Alzheimer’s disease (AD) is characterized by chronic deposition of β-amyloid (Aβ) in the brain, progressive neurodegeneration and consequent cognitive and behavioral deicits that typify the disease. Astrocytes are pivotal in this process because they are activated in the attempt to digest Aβ which starts a neuroinlammatory response that further contributes to neurodegeneration. The intestine is a good source of astrocytes-like cells-referred to as enteric glial cells (eGCs). Here we show that the autologous transplantation of eGCs into the brain of Aβ-injected rats arrested the development of the disease after their engraftment. Transplanted EGCs showed anti-amyloidogenic activity, embanked Aβ-induced neuroinlammation and neurodegeneration, and released neutrophic factors. The overall result was the amelioration of the pathological hallmarks and the cognitive and behavioral deicits typical of Aβ-associated disease. our data indicate that autologous eGCs transplantation may provide an eicient alternative for applications in cell-replacement therapies to treat neurodegeneration in AD. A chronic, progressive imbalance in either Aβ production or removal rates due to malfunctioning resident astro- cytes in the brain plays a crucial role in AD progression 1,2 . In response to Aβ deposition, resident astrocytes are activated, proliferate and migrate to the site of amy- loid plaques to digest Aβ 3,4 . However, during this process, astrocytes also release proinlammatory factors that intensify the progressive neuronal degeneration and loss in the Alzheimer’s disease (AD) brain 5–7 . So far, few attempts have been made with the possible use of astrocyte-targeted treatments, with noticeable success in animal models of AD 4,6–8 . In particular, the idea of replacing malfunctioning astrocytes with brand new ones, proposed by Pihlaja et al. 4 , is very challenging and bears a huge therapeutic potential. However, many limitations exist on allogenic transplantation and its potential applications to humans 9,10 . A possible strategy could be the use of astrocytes-like cells, namely enteric glial cells (EGCs) in the intestine, as these share many morphological and functional features with cerebral astrocytes 11 . Here we evaluated the eicacy of the autograt of EGCs in the brain of a rat model of Aβ -induced AD (Fig. 1a). We irst demonstrated astrocyte activation following the infusion of Aβ (1–42) peptide in rat brains. Speciically, ater Aβ -plaque deposit and growth in both the cortex and hip- pocampus (Fig. 1b) we found that astrocytes (GFAP positive cells) surrounded Aβ deposits, conirming previous 1 Department of Physiology and Pharmacology, “La Sapienza” University of Rome, italy. 2 Department of clinical Medicine and Surgery, University of naples “federico ii”, naples, italy. 3 Laboratory for enteric neuroScience (LenS), tARGiD, University of Leuven, Leuven, Belgium. 4 Department of neurology, Beth israel Deaconess Medical center, Harvard Medical School, Boston, Massachusetts, USA. 5 institute of experimental endocrinology and Oncology-cnR. naples, italy. * these authors contributed equally to this work. correspondence and requests for materials should be addressed to G.E. (email: giuseppe.esposito@uniroma1.it) or G.S. (email: sarnelli@unina.it) Received: 24 June 2015 Accepted: 17 February 2016 Published: 04 March 2016 opeN