Neurogenesis in the Diseased Adult Human Brain: New Therapeutic Strategies for Neurodegenerative Diseases

Abstract

Worldwide attention is presently focused on the potential use of exogenous progenitor cells as a source of cells for transplantation therapy in neurodegenerative diseases such as Huntington's and Parkinson's disease. Because controversy has surrounded the use of human fetal and embryonic tissue for the purposes of experimentation and transplantation, new sources of cells for transplantation have been sought. Less controversial, and probably more notable, is the recent demonstration of the presence of endogenous progenitor cells in the adult human brain in both the hippocampus and the subependymal layer overlying the caudate nucleus. 1,2 These observations indicate that, contrary to the well rehearsed dogma, the adult human brain contains progenitor cells that are capable of producing new neurons. This raises the possibility that endogenous neural progenitor cells may provide an alternative strategy for cell replacement therapy through the enhancement of endogenous neural replacement mechanisms to produce new neurons that replace the cells that die in neurodegenerative diseases.We have recently demonstrated that in Huntington's disease (a progressive autosomal dominant neurodegenerative disorder that principally affects the striatum) there are significantly more dividing cells in the subependymal layer (the neurogenic layer that overlies the striatum) compared with controls. 2 In this study we have shown that about 5% of the cells that have recently divided become neurons and others become glial cells. In this case, the trigger for the increased cell production in the Huntington's disease brain appears to be the death of neurons in the striatum because as cell death advances in Huntington's disease more dividing cells are present in the subependymal layer of the diseased brain. However, in Huntington's disease it would appear that the increase in cell proliferation and neurogenesis is too little too late. If the proliferation, migration and differentiation of endogenous progenitor cells could be pharmacologically enhanced then progenitor cells may more effectively replace the specific cells that die in neurodegenerative diseases.Neural progenitor cells have been shown to respond to a variety of mitogenic growth/trophic factors and cytokines in vivo such as epidermal growth factor (EGF), fibroblast growth factor (FGF-2), nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), erythropoietin (EPO) and others by facilitating the proliferation, migration and differentiation of progenitor cells in the adult central nervous system. [3][4][5][6][7][8][9][10][11][12][13][14] In one such in vivo study the growth factor EGF was infused into the lateral ventricle of adult mice; the results demonstrated a dramatic increase in the number of proliferating cells in the subependymal layer of the lateral ventrical. 9 Immunohistochemical analysis revealed that more than 95% of the cells present in the subependymal layer were immunopositive for the EGF receptor and were also nestin...

Extensive changes in DNA methylation are associated with expression of mutant huntingtin

“…This finding is in line with the recent literature that perturbed neurogenesis is involved in the pathogenesis of HD (40). Increased neurogenesis in the SVZ has been observed in postmortem HD brain and mouse models (41)(42)(43)(44). These findings may suggest a delayed and insufficient endogenous reaction of brain tissue to counteract the severe neuropathology.…”

A histochemical and immunohistochemical analysis of the subependymal layer in the normal and Huntington's disease brain

“…Interestingly, there was no increase in the density of the cells in HD compared with normal SEL but there was an increase in cell number in the HD SEL; thus the extra cells occupied the space of the thickened SEL. Our previous studies have demonstrated a population of cells that are located homogenously across the SEL and are GFAP positive glial cells, thus the type B cells appear to correspond to these cells (Curtis et al, 2003a(Curtis et al, , 2003b. Also, in our previous studies we reported bIIItubulin positive cells in the lower SEL (close to the myelin layer); the location and staining pattern is very similar to the type C cells described here (Curtis et al, 2003a(Curtis et al, , 2003b.…”

“…Our previous studies have demonstrated a population of cells that are located homogenously across the SEL and are GFAP positive glial cells, thus the type B cells appear to correspond to these cells (Curtis et al, 2003a(Curtis et al, , 2003b. Also, in our previous studies we reported bIIItubulin positive cells in the lower SEL (close to the myelin layer); the location and staining pattern is very similar to the type C cells described here (Curtis et al, 2003a(Curtis et al, , 2003b. Our previous studies have not demonstrated a suitable antibody for detection of type A cells in the human brain, however analysis of histochemically stained sections has revealed a similar population of type A cells as in the rodent brain (Doetsch et al, 1997;Curtis et al, 2003aCurtis et al, , 2003b.…”

“…We have previously demonstrated that the adult human SEL contains progenitor cells that proliferate and form new neurons in response to Huntington's disease (HD) (Connor et al, 2001;Curtis et al, 2003aCurtis et al, , 2003b. However, the SEL in www.elsevier.com/locate/jchemneu Journal of Chemical Neuroanatomy 30 (2005) [55][56][57][58][59][60][61][62][63][64][65][66] the adult human brain has not been previously described in terms of its detailed morphological and histochemical staining characteristics neither has it been described in the HD brain where the underlying caudate nucleus undergoes extensive degeneration (Ferrante et al, 1991;Hedreen and Folstein, 1995;Aylward et al, 1996;Vonsattel and DiFiglia, 1998).…”

The Diversity of GABAA Receptor Subunit Distribution in the Normal and Huntington's Disease Human Brain1

“…In the normal human SVZ, neural precursors have been identified (Curtis et al, 2005;Kam et al, 2009) using PCNA as a marker for proliferating cells coupled with neuronal stem cell markers to identify their neuronal phenotype. In Huntington's disease brain, an increase in cell proliferation was found in the SVZ with evidence for increased neurogenesis and increasing thickness of the SVZ with increasing grade (Curtis, Connor, & Faull, 2003); that is, with increased cell death in the CN, there is increased neurogenesis in the SVZ. This raises the exciting possibility of stimulating the production of new neurons from precursors in the SVZ and subsequent migration directly or via the rostral migratory stream (Curtis et al, 2007) into the cell-depleted HD striatum as a possible therapy for HD.…”