Avaliação histológica e ultra estrutural de regiões encefálicas em um modelo murinho da Doença de Huntington tratado com uma droga potencialmente neuroprotetora, CDPPB

Abstract

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion at the Huntingtin protein. Patients with HD show progressive neuronal death which leads to motor deficit, loss of cognitive functions and psychiatric alterations. One of the main causes of the neuronal loss is the excitotoxicity caused by glutamate. Recent studies show that the mGluR5 upon CDPPB modulation are neuroprotective. Once the neuronal death is a key factor to understand HD development, in this study we evaluated in the cerebral cortex, hippocampus and cerebellum, the cell loss, as well as alterations in the cell bodies of the cerebral cortex. In addition, we have analyzed the ultrastructure of the synapses at the cerebral cortex and hippocampus. We used in this study WT, BACHD and BACHD mice treated with CDPPB for 18 weeks. Our results showed a reduction in the number of cells in the cerebral cortex and in the dentate gyrus of the hippocampus from BACHD mice. The total number of Purkinje neurons were similar in both experimental groups. The ultrastructural characteristics of the cerebral cortex that characterize cells under degenerative process (accumulation of lipofuscin bodies), showed and enhancement of these structures in the BACHD mice compared to WT. The treatment with CDPPB partially reduced these findings. At last, we have evaluated a possible impairment at the synapses of the cerebral cortex and hippocampus. We found that the pre-synaptic area, the number of vesicles per area and the number of vesicles at 200nm from the active zone (A.Z) were both reduced in BACHD mice compared to WT. However, the treatment only partially reverted the number of vesicles per area. The synapses from the hippocampus were not different when compared to control. Therefore, our data show the role of the mutated Htt in cell loss and synaptic alterations, furthermore our study open new routes of investigation on the efficiency of the CDPPB treatment, especially in the creation of new treatments based on positive allosteric modulators (PAMs).