Pro-NGF Disrupts Adult Neurogenesis in Humans and Mice Affected by Alzheimer's Disease

Abstract

In recent decades, neurogenesis in adult brain has been well demonstrated in a number of animal species, including humans. Interestingly, work with rodents has shown that adult neurogenesis in the dentate gyrus (DG) of the hippocampus is vital for some cognitive aspects, as increasing neurogenesis improves memory while its disruption triggers the opposite effect. Adult neurogenesis declines with age and has been suggested to play a role in impaired progressive learning and memory loss seen in Alzheimer’s disease (AD). Therefore, therapeutic strategies designed to boost adult hippocampal neurogenesis may be beneficial for the treatment of AD. The precursor forms of neurotrophins, such as pro-NGF, display remarkable increase during AD in the hippocampus and entorhinal cortex. In contrast to mature NGF, pro-NGF exerts adverse functions in survival, proliferation and differentiation. Hence, we hypothesized that pro-NGF and its receptor p75NTR contribute to disrupting adult hippocampal neurogenesis during AD. In this study, we took advantage of the availability of mouse models of AD (APP/PS1) and AD human samples to address the role of pro-NGF/p75NTR signalling in different aspects of adult neurogenesis. Neuroprogenitors of adult mice and human DG samples were identified by immunofluorescence with doublecortin (DCX) antibodies. Interestingly, DCX + progenitors in healthy humans and control animals express p75 neurotrophin receptor (p75NTR). However, this expression is notably decreased in AD conditions. In APP/PS1 mice, memory and cognition were severely impaired. In order to assess the contribution of the pro-NGF/p75NTR pathway to these memory deficits, we injected pro-NGF neutralizing antibodies (ANTI-PRONGF) into the DG of control and APP/PS1 mice which memory was evaluated in Morris water maze test. We observed that anti-pro-NGF injection significantly improved the performance of APP/PS1 animals, but not controls. Interestingly, improved memory in APP/PS1 animals after injection of ANTI-PRONGF correlated with an increase in DCX + progenitors in the DG region of these animals. In summary, our results suggest that pro-NGF is involved in disrupting spatial memory in AD, at least in part by blocking adult neurogenesis. Moreover, we propose that adult neurogenesis alteration could serve as alternative approach towards understanding AD pathology, and additionally offer pro-NGF/p75NTR signalling as a promising therapeutic target.