Adult Rat Dopaminergic Neurons Dominate In Striatum And Embryonic Mouse Ventral Brain Development Proteomics Research

During neurodegenerative processes, the injured cells will promote their target tissue to release neurotrophic factors. In this study, we characterized trophic effects of the striatum of adult Sprague-Dawley rat following 6-hydroxydopamine lesions on survival of fetal DA neurons. Treatment of ventral mesencephalic cultures with the striatal extracts delayed DA cell death in dose-dependent manner. In order to better understand the molecular events occurring in the denervated target tissue, we investigated the variations of protein expression in the dopamine-depleted striatum. The rat striatum, ipsilateral to the lesion was analyzed by two-dimensional gel electrophoresis followed by matrix assisted laser desorption/ionization-time of flight mass spectrometry. Seven proteins were up-regulated (188.1-750% compared to control) in response to the lesion, including amyloid precursor-like protein 2 (APLP2), kininogen, glucokinase, tropomyosin α chain, type brain-1 and calpactin Ⅰlight chain; whilst four proteins , including neural epidermal growth factor-like 2, minichromosome maintenance 6, and thyroid hormone receptor β-2, were down-regulated (to between 36% and 59% of levels in sham-operated controls). Three proteins that did not match with available data in the SWISS-PROT protein database were also determined. Immunohistochemical analysis demonstrated colocalization of APLP2 and tyrosine hydroxylase in the nigral neurons. Moreover, reduction of APLP2-positive neurons in the substantia nigra pars compacta as well as the increases in the substantial nigra pars reticulata and in the striatum were observed. Furthermore, the conditioned medium of the Chinese hamster ovary cells over-expressing APLP2-751 (chondroitin sulphate-modified), but not APLP2-763 (nonchondroitin sulphate-modified), was able to increase the number of the tyrosine hydroxylase-positive neurons in fetal mesencephalic cultures. These results suggest that the expression of APLP2, a protein that has been thought to be associated with Alzheimer's disease, is up-regulated in the striatum following dopaminergic denervation. They also support the view that chondroitin sulphate-modified APLP2 protein may play an important role in protection and repairation of dopaminergic neuron.