Increased cell proliferation and neurogenesis in the adult human Huntington's disease brain

Abstract

Neurogenesis has recently been observed in the adult human brain, suggesting the possibility of endogenous neural repair. However, the augmentation of neurogenesis in the adult human brain in response to neuronal cell loss has not been demonstrated. This study was undertaken to investigate whether neurogenesis occurs in the subependymal layer (SEL) adjacent to the caudate nucleus in the human brain in response to neurodegeneration of the caudate nucleus in Huntington's disease (HD). Postmortem control and HD human brain tissue were examined by using the cell cycle marker proliferating cell nuclear antigen (PCNA), the neuronal marker ␤III-tubulin, and the glial cell marker glial fibrillary acidic protein (GFAP). We observed a significant increase in cell proliferation in the SEL in HD compared with control brains. Within the HD group, the degree of cell proliferation increased with pathological severity and increasing CAG repeats in the HD gene. Most importantly, PCNA ؉ cells were shown to coexpress ␤III-tubulin or GFAP, demonstrating the generation of neurons and glial cells in the SEL of the diseased human brain. Our results provide evidence of increased progenitor cell proliferation and neurogenesis in the diseased adult human brain and further indicate the regenerative potential of the human brain.A particularly exciting development in the treatment of neurodegenerative diseases is the suggestion from both animal and human studies that transplantation of embryonic neurons or stem cells offer a potential treatment strategy for neurodegenerative disorders such as Parkinson's disease, Huntington's disease (HD), and Alzheimer's disease (1, 2). Although in recent years the transplantation of embryonic cells into the diseased human brain has emerged from the realm of the theoretical to that of the practical, it is associated with ethical, technical, and immunological problems (2). Thus, the demonstration of endogenous stem͞progenitor cells in the hippocampus and the subependymal layer (SEL) of the basal ganglia in the adult mammalian brain has raised the exciting possibility that these undifferentiated cells may be able to generate neurons for cell replacement in neurodegenerative diseases such as HD. Indeed, neural stem cells in the rodent brain SEL adjacent to the caudate nucleus have recently been shown to proliferate and differentiate into neurons (3-5), suggesting they may provide a source of replacement neurons. In this regard it is especially interesting that recent studies (6) on the normal adult human brain have shown evidence of neurogenesis in the hippocampus, but no previous study has yet shown neurogenesis in the SEL of the normal or diseased human brain. Here, we have examined whether progenitor cell proliferation and neurogenesis occur in the SEL adjacent to the caudate nucleus in response to cell death in the caudate nucleus of the adult human HD brain. The results demonstrate increased progenitor cell proliferation and neurogenesis in the SEL of the HD brains indicating that the diseased human brai...

Stem cell factor and mesenchymal and neural stem cell transplantation in a rat model of Huntington's disease

“…Endogenous neural progenitors have the ability to proliferate and/or migrate towards brain lesions in various pathological models as well as in the diseased human brain (Arvidsson et al, 2002;Curtis et al, 2003;Sun et al, 2004;Tattersfield et al, 2004). Exogenous stem cells also display an ability to migrate and survive in the lesioned parenchyma following transplantation (Eglitis et al, 1999;Mahmood et al, 2001;Imitola et al, 2004;Hill et al, 2004).…”

“…Increased neurogenesis is a common feature of various neurological conditions such as stroke, Alzheimer's disease and Huntington's disease (Curtis et al, 2003;Kokaia and Lindvall, 2003;Jin et al, 2004). However, its exact functional consequence remains unclear (Emsley et al, 2005) as the recruitment of endogenous neural stem cells is clearly insufficient to compensate for the progressive cell loss that occurs.…”

“…Recently, it has also been demonstrated that environmental changes occurring during HD or following quinolinic acid (QA)-induced striatal lesions in a rat model reminiscent of HD (Beal et al, 1986; see also Guidetti et al, 2004) may stimulate in situ neurogenesis (Curtis et al, 2003;Tattersfield et al, 2004). Although the recruitment of endogenous neural stem cells in response to injury is clearly insufficient to compensate for progressive cell loss, it indicates that factors supporting the survival of stem cells are present within the lesioned area.…”

Adult neurogenesis is functionally associated with AD-like neurodegeneration

“…Moreover, certain acute brain injuries such as ischemia, hypoxia, seizures, and trauma increase neurogenesis (Kokaia and Lindvall, 2003, Rice, et al, 2003, Itoh, et al, 2005, Overstreet-Wadiche, et al, 2006, Qiu, et al, 2007, suggesting that neurogenesis may work as a protective mechanism for the brain. Interestingly, enhanced neurogenesis was recently found in brains of neurodegenerative diseases including Huntington's disease (Curtis, et al, 2003), Parkinson's disease (Hoglinger, et al, 2004), and AD (Jin, et al, 2004a). However, neither the course of neurogenesis during the neurodegenerative processes nor the functional significance of neurogenesis in neurodegeneration is well understood.…”

Advances in Gene Therapy for Movement Disorders

“…The degree of cell proliferation increases with the severity of the disease pathology and the number of CAG repeats in HTT. 99 However, these new immature neurons either die or differentiate into glial cells.…”