Nerve growth factor promotes survival of new neurons in the adult hippocampus

Abstract

Exogenously provided NGF enhances cognitive performance in impaired rodents and humans and is currently a promising compound for the treatment of dementia. To investigate whether NGF-dependent cognitive improvement may be due in part to increased hippocampal neurogenesis, adult and aged male rats were treated with NGF or vehicle intracerebroventricularly for 6 or 20 days followed by evaluation of cholinergic parameters and hippocampal neurogenesis. We show that NGF increases hippocampal cholinergic activity as rapidly as 3 days after initiation of treatment. NGF treatment for 6 days did not affect proliferation of progenitor cells in the dentate gyrus granule cell layer (GCL). However, continuous NGF infusion enhanced survival of new neurons in the GCL of young adult, but not aged rats. Taken together, these findings suggest that NGF, likely mediated through increased cholinergic tone, promotes neurogenesis in the adult hippocampus, which may relate to the nootropic action of NGF.

Introduction

With the continued expansion of the aged population, there is an urgent need for effective therapies for neurodegenerative disorders involving cognitive decline, such as Alzheimer’s disease (AD). Presently, most therapies for AD are aimed at enhancing or restoring cholinergic function. The neurotrophin nerve growth factor (NGF) promotes the growth, differentiation and survival of cholinergic neurons in the basal forebrain and is thus ideally suited as a cholinergic therapeutic (Winkler et al., 1998). Exogenous NGF rescues cholinergic neurons in the basal forebrain and improves cognitive function in impaired, aged or cholinergically lesioned rats (Fischer et al., 1987, Fischer, 1994, Markowska et al., 1994, Pizzo and Thal, 2004, Jakubowska-Dogru and Gumusbas, 2005). A recent report shows that transplantation of fibroblasts genetically modified to secrete NGF led to a slowing of cognitive decline in a phase 1 clinical trial performed on patients suffering from mild AD (Tuszynski et al., 2005). Additional clinical trials using in vivo gene therapy of NGF are underway. The behavioral effects of NGF are correlated with the degree of cholinergic hypertrophy caused by NGF (Gustilo et al., 1999), but the precise mechanisms behind the nootropic actions of NGF are still poorly understood and may not be restricted to cholinergic enhancement.

Generation of new neurons in adult life takes place in at least two brain regions, the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the hippocampus. Neurotrophins are extracellular signaling molecules involved in the maintenance and support of neurons, which make them attractive candidates for the regulation of neurogenesis, particularly the survival aspect. The most extensively studied neurotrophin, brain derived neurotrophic factor (BDNF), seems to be a potent mediator of hippocampal neurogenesis in models of depression, caloric restriction, transgenic models as well as direct intrahippocampal administration (D’Sa and Duman, 2002, Lee et al., 2002, Sairanen et al., 2005, Scharfman et al., 2005). Direct effects of neurotrophin-3 (NT-3) administration are less well studied, but similar to BDNF it has been linked to an increase in hippocampal neurogenesis after caloric restriction (Lee et al., 2002), and impaired neuronal differentiation has been reported in NT-3 conditional knock-out mice (Shimazu et al., 2006). Since hippocampal neurogenesis has been linked to learning and memory in some model systems (Shors et al., 2002, Madsen et al., 2003, Snyder et al., 2005), increased neurogenesis could be one of the mechanisms behind the cognitive improvement seen with NGF treatment. However, the effects of NGF on hippocampal neurogenesis have not been reported. Therefore, we investigated whether the cognitive improvement associated with NGF treatment could be mediated, at least in part, by increased hippocampal neurogenesis. Since NGF has minimal penetration across the blood–brain barrier (Loy et al., 1994), it cannot be delivered peripherally. We have previously used intracerebroventricular (ICV) delivery of NGF to increase cholinergic functioning and found a robust improvement of performance in hippocampal-dependent memory tasks (Pizzo and Thal, 2004).

Hippocampal neurogenesis is robust in the young adult and persists into old age even though it is diminished to approximately 10% of adult levels (Kuhn et al., 1996). As aging is one of the best models of cognitive decline available, we wanted to compare the effect of NGF on neurogenesis in the young adult to that in the aged brain. Therefore, we investigated the effects of continuous ICV infusion of NGF on hippocampal neurogenesis in young adult and aged rats and assessed its effects on proliferation, survival and differentiation. We also studied whether NGF might impact cell death in the dentate gyrus as measured by a marker for apoptosis.