proNGF Involvement in the Adult Neurogenesis Dysfunction in Alzheimer’s Disease

Abstract

In recent decades, neurogenesis in the 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 p75 neurotrophin receptor (p75NTR) contribute to disrupting adult hippocampal neurogenesis during AD. To test this hypothesis, in this study, we took advantage of the availability of mouse models of AD (APP/PS1), which display memory impairment, and AD human samples to address the role of pro-NGF/p75NTR signaling in different aspects of adult neurogenesis. First, we observed that DG doublecortin (DCX) + progenitors express p75NTR both, in healthy humans and control animals, although the percentageof DCX+ cells were significantly reduced in AD. Interestingly, the expression of p75NTR in these progenitors was significantly decreased in AD conditions compared to controls. In order to assess the contribution of the pro-NGF/p75NTR pathway to the memory deficits of APP/PS1 mice, we injected pro-NGF neutralizing antibodies (anti-proNGF) into the DG of control and APP/PS1 mice and animals are subjected to Morris water maze test. Intriguingly, we observed that anti-pro-NGF significantly restored memory performance of APP/PS1 animals and significantly increased the percentage of 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 should be taken into consideration for better understanding of AD pathology. Additionally, we provide a new molecular entry point (pro-NGF/p75NTR signaling) as a promising therapeutic target in AD.

Manual acupuncture alleviates bladder dysfunction by up-regulating expression of NGF and its receptors in bladder tissue of diabetic neurogenic bladder rats

“…There are two receptors for NGF, tropomyosin receptor kinase A (TrkA) and p75neurotrophinreceptor (p75NTR). When NGF is combined with TrkA or p75NTR, it can promote the growth of axons and maintain the growth and survival of neuronal cells (10,11).According to the latest studies, the levels of NGF and TrkA, p75NTR decreased in the bladder tissue of DNB rats (12)(13)(14). NGF regulates the levels of neuropeptides such as substance P (SP) and calcitonin gene-related peptides (CGRP) to some extent, which are associated with the micturition re ex.…”

Molecular Signals and Genetic Regulations of Neurological Disorders

“…Several hypotheses have been proposed to explain the complex pathophysiology of AD, including altered neurogenesis and neuroinflammation. Olabiyi et al, 2021 [ 2 ] explored the possibility to boost adult hippocampal neurogenesis to obtain therapeutic gain in AD. Neurogenesis is mediated by neurotrophins, a family of secreted growth factors, of which nerve growth factor (NGF) and brain-NGF are the best known.…”