proNGF Involvement in the Adult Neurogenesis Dysfunction in Alzheimer’s Disease
In recent decades, neurogenesis in the adult brain has been well demonstrated in anumber of animal species, including humans. Interestingly, work with rodents has shown that adultneurogenesis in the dentate gyrus (DG) of the hippocampus is vital for some cognitive aspects, asincreasing neurogenesis...
| Autores: | , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:10459.1/83631 |
| Acceso en línea: | https://doi.org/10.3390/ijms221910744 http://hdl.handle.net/10459.1/83631 |
| Access Level: | acceso abierto |
| Palabra clave: | Alzheimer’s disease Adult neurogenesis pro-NGF p75 Dentate gyrus Memory impairment |
| Sumario: | In recent decades, neurogenesis in the adult brain has been well demonstrated in anumber of animal species, including humans. Interestingly, work with rodents has shown that adultneurogenesis in the dentate gyrus (DG) of the hippocampus is vital for some cognitive aspects, asincreasing neurogenesis improves memory, while its disruption triggers the opposite effect. Adultneurogenesis declines with age and has been suggested to play a role in impaired progressive learningand memory loss seen in Alzheimer’s disease (AD). Therefore, therapeutic strategies designed toboost adult hippocampal neurogenesis may be beneficial for the treatment of AD. The precursor formsof neurotrophins, such as pro-NGF, display remarkable increase during AD in the hippocampusand 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 neurotrophinreceptor (p75NTR) contribute to disrupting adult hippocampal neurogenesis during AD. To test thishypothesis, 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/p75NTRsignaling 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 are significantly reduced in AD. Interestingly, the expression of p75NTR in theseprogenitors is significantly decreased in AD conditions compared to controls. In order to assessthe contribution of the pro-NGF/p75NTR pathway to the memory deficits of APP/PS1 mice, weinjected pro-NGF neutralizing antibodies (anti-proNGF) into the DG of control and APP/PS1 miceand 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 increasethe percentage of DCX+ progenitors in the DG region of these animals. In summary, our resultssuggest that pro-NGF is involved in disrupting spatial memory in AD, at least in part by blockingadult neurogenesis. Moreover, we propose that adult neurogenesis alteration should be taken intoconsideration for better understanding of AD pathology. Additionally, we provide a new molecularentry point (pro-NGF/p75NTR signaling) as a promising therapeutic target in AD. |
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