Neural progenitor cells in the Huntington's Disease human brain

Abstract

The recent demonstration of endogenous progenitor cells in the adult mammalian brain raises the exciting possibility that these undifferentiated cells may be able to generate new neurons for cell replacement in diseases such as Huntington's disease (HD). Previous studies have shown that neural stem cells in the rodent brain subependymal layer (SEL), adjacent to the caudate nucleus, proliferate and differentiate into neurons and glial cells but no previous study has characterised the human SEL or shown neurogenesis in the diseased human brain. In this study, histochemical and immunohistochemical techniques were used to demonstrate the regional anatomy and staining characteristics of the normal and HD brain SEL using light and laser scanning confocal microscopy. The results demonstrated that the normal and HD SEL contained migrating neuroblasts, glial cells and precursor cells but there were more of each cell type present in the HD brain, and that the increase in cell numbers correlated with HD neuropathological grade. The normal and HD SEL was stained with a proliferative marker, proliferating cell nuclear antigen (PCNA), to label dividing cells. The results showed a significant increase in the number of dividing cells in the HD brain that correlated with HD grade and with CAG repeat length. Furthermore, the results showed that neurogenesis had occurred in the SEL as evidenced by co-localisation of PCNA and the neuronal marker βIII-tubulin. Also, gliogenesis had occurred in the SEL as evidenced by the co-localisation of PCNA with the glial marker GFAP. These studies also revealed a 2.6 fold increase in the number of new neurons in the HD SEL. PCNA positive cells were distributed throughout the SEL overlying the caudate nucleus but most notably the ventral and central regions of the SEL adjacent to the caudate nucleus contained the highest number of proliferating cells. I examined the SEL for mature cell markers and demonstrated many of the same cell types that are present in the normal striatum. With the exception of neuropeptide Y (NPY) neurons, there was a reduction in the number of mature neurons in the HD SEL. The NPY neurons were more abundant in the HD SEL suggesting they play a role in progenitor cell proliferation. The results in this thesis provide evidence of increased progenitor cell proliferation and neurogenesis in the diseased adult human brain and indicate the regenerative potential of the human brain. These findings may be of major relevance to the development of therapeutic approaches in the treatment of neurodegenerative diseases.