Abstract
The presence of ongoing neurogenesis in the adult mammalian brain raises the exciting possibility that endogenous progenitor cells could be used therapeutically for repair of neuronal loss associated with brain disease or injury. While previous studies have demonstrated that the adult brain has the potential for self-repair, it is apparent that the level of neurogenesis observed is insufficient to compensate for the progressive cell loss that occurs during brain injury and disease. In order for endogenous progenitor cells to be useful therapeutically, methods need to be developed to augment the process of neurogenesis and direct progenitor cells to proliferate, migrate and generate new neurons in specific areas of neuronal cell loss. Using in vivo gene transfer, we investigated the effect of Brain-Derived Neurotrophic Factor (BDNF) on the migration, differentiation and survival of endogenous progenitor cells in both the normal adult rat brain and the quinolinic acid (QA) lesion rat model of Huntington's disease (HD). We have developed a recombinant AAV vector encoding the human BDNF transgene under the control of the CBA constitutive promoter. Adult rats received unilateral stereotaxic injections of either AAV-BDNF, the control vector AAV-luciferase or sterile PBS into the anterior subventricular zone (SVZ). Three weeks later, the rats received daily injections of the mitotic marker bromodeoxyuridine (BrdU; 150 mg/kg i.p.) for 21 days in order to identify newly generated cells. Half of the rats also received a unilateral striatal injection of QA (50 nmol) in order to model HD. In the normal adult rat brain, BDNF over-expression had no effect on the number of BrdU labelled cells in the SVZ or striatum but resulted in a significant increase in BrdU labelling in the rostral migratory stream (RMS) compared to untreated animals (p|[le]|0.01). In untreated animals that received a striatal QA lesion we observed a significant reduction in the number of BrdU labelled cells in the SVZ and RMS compared to unlesioned animals (p|[le]|0.05) 21 days after lesioning, suggesting a chronic alteration in the dynamics of progenitor cell proliferation in response to QA lesioning. While BDNF over-expression did not alter the reduction in BrdU labelling observed in the RMS of QA lesioned animals, BDNF significantly increased the level of BrdU labelling in the SVZ of QA lesioned animals to that observed in unlesioned animals (p|[le]|0.01). BDNF also greatly induced the level of BrdU-immunoreactivity observed in the QA lesioned striatum compared to untreated animals (p|[le]|0.001). Furthermore, 9 weeks following QA lesioning we observed that BDNF over-expression had greatly enhanced the level of striatal neurogenesis observed in QA lesioned animals compared to untreated animals. These results demonstrate that over-expression of BDNF in the SVZ substantially augments the survival, migration and neuronal differentiation of progenitor cells in both neurogenic and non-neurogenic regions of the normal or QA lesioned adult rat brain, supporting the potential therapeutic use of endogenous neural progenitor cells for the treatment of HD.
Published Version
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