Neuroprotecitve effect of NPY in in vitro models of Alzheimer's disease, focus on neurotrophins

Abstract

neurodegenerative disorder associated with an expanded polyglutamine tract within the ataxin-3 protein, and characterized by progressive impairment of motor coordination, associated to neurodegeneration of specific brain regions including cerebellum and striatum. The currently available therapies do not allow modification of disease progression. NPY has been shown to exert potent neuroprotective effects by multiple pathways associated to the MJD mechanisms of disease. Thus, we evaluated NPY levels in MJD and investigated whether raising NPY by gene transfer would alleviate neuropathological and behavioural deficits in cerebellar and striatal mouse models of the disease. For that, a cerebellar transgenic and a striatal lentiviral-based models of MJD were used. NPY overexpression in the affected brain regions in these two mouse models was obtained by stereotaxic injection of adeno-associated viral vectors encoding NPY; 8 weeks after viral injection, balance and motor coordination behaviour and neuropathology were analysed. NPY levels were decreased in two MJD patients' cerebella and in striata and cerebella of disease mouse models. Furthermore, NPY overexpression alleviated motor coordination impairments and attenuated related neuropathological cerebellar parameters and decreasing mutant ataxin-3 aggregation. Additionally, NPY mediated increase of brain-derived neurotrophic factor levels and decreased neuroinflammation markers. Our data suggest that NPY is a potential therapeutic strategy for MJD. This work was supported by The Richard Chin and Lily Lock Research Fund; E-Rare4/0003/2012; FCT SFRH/BD/74993/2010, SFRH/BD/87404/ 2012, SRFH/BPD/87341/2012; QREN – Projeto Mais Centro – New Strategies to Manage Brain Diseases CENTRO-07-ST24-FEDER-002002, FEDER and COMPETE – UID/NEU/04539/2013.