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Article

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

1
Molecular Developmental Neurobiology Group, IRBLleida-UDL Rovira Roure 82, 25198 Lleida, Spain
2
Institute of Molecular Psychiatry, Medical Faculty, University of Bonn, 53127 Bonn, Germany
3
Departament de Patologia i Terapèutica Experimental, Universitat de Barcelona, 08007 Barcelona, Spain
4
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Hospitalet de Llobregat, 08900 Barcelona, Spain
5
Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, 31062 Toulouse, France
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Emanuele Rocco Villani and Emanuele Marzetti
Int. J. Mol. Sci. 2021, 22(19), 10744; https://doi.org/10.3390/ijms221910744
Received: 26 August 2021 / Revised: 28 September 2021 / Accepted: 29 September 2021 / Published: 4 October 2021
(This article belongs to the Special Issue Molecular Signals and Genetic Regulations of Neurological Disorders)
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 percentage of DCX+ cells are significantly reduced in AD. Interestingly, the expression of p75NTR in these progenitors is 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 a Morris water maze test. Intriguingly, we observed that anti-pro-NGF significantly restored memory performance of APP/PS1 animals and significantly increase 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. View Full-Text
Keywords: Alzheimer’s disease; adult neurogenesis; pro-NGF; p75; dentate gyrus; memory impairment Alzheimer’s disease; adult neurogenesis; pro-NGF; p75; dentate gyrus; memory impairment
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MDPI and ACS Style

Olabiyi, B.F.; Fleitas, C.; Zammou, B.; Ferrer, I.; Rampon, C.; Egea, J.; Espinet, C. proNGF Involvement in the Adult Neurogenesis Dysfunction in Alzheimer’s Disease. Int. J. Mol. Sci. 2021, 22, 10744. https://doi.org/10.3390/ijms221910744

AMA Style

Olabiyi BF, Fleitas C, Zammou B, Ferrer I, Rampon C, Egea J, Espinet C. proNGF Involvement in the Adult Neurogenesis Dysfunction in Alzheimer’s Disease. International Journal of Molecular Sciences. 2021; 22(19):10744. https://doi.org/10.3390/ijms221910744

Chicago/Turabian Style

Olabiyi, Bolanle Fatimat, Catherine Fleitas, Bahira Zammou, Isidro Ferrer, Claire Rampon, Joaquim Egea, and Carme Espinet. 2021. "proNGF Involvement in the Adult Neurogenesis Dysfunction in Alzheimer’s Disease" International Journal of Molecular Sciences 22, no. 19: 10744. https://doi.org/10.3390/ijms221910744

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