Impact of neurodegenerative diseases on human adult hippocampal neurogenesis

Disrupted hippocampal performance underlies psychiatric comorbidities and cognitive impairments in patients with neurodegenerative disorders. To understand the contribution of adult hippocampal neurogenesis (AHN) to amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, dementia with Lewy bodies, and frontotemporal dementia, we studied postmortem human samples. We found that adult-born dentate granule cells showed abnormal morphological development and changes in the expression of differentiation markers. The ratio of quiescent to proliferating hippocampal neural stem cells shifted, and the homeostasis of the neurogenic niche was altered. Aging and neurodegenerative diseases reduced the phagocytic capacity of microglia, triggered astrogliosis, and altered the microvasculature of the dentate gyrus. Thus, enhanced vulnerability of AHN to neurodegeneration might underlie hippocampal dysfunction during physiological and pathological aging in humans.Fil: Terreros Roncal, J.. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Moreno Jiménez, E.P.. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Flor García, M.. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Rodríguez Moreno, C.B.. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Trinchero, Mariela Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Cafini, F.. Universidad Europea de Madrid; EspañaFil: Rábano, A.. No especifíca;Fil: Llorens Martín, M.. Universidad Autónoma de Madrid; Españ

Soluble Tau has devastating effects on the structural plasticity of hippocampal granule neurons

Tau is a neuronal microtubule-associated protein with countless physiological functions. Although the detrimental effects of insoluble aggregated Tau have been widely studied, recent evidence supports the notion that soluble Tau (composed mostly of monomers and dimers) is also toxic for neurons. Here we evaluated the long-term impact of a single stereotaxic injection of human soluble Tau on hippocampal granule neurons in mice. At the ultrastructural level, soluble Tau reduced the number of afferent synapses and caused a dramatic depletion of synaptic vesicles both in afferent and efferent synapses. Furthermore, the use of an RFP-expressing retrovirus revealed that soluble Tau altered the morphology of newborn granule neurons and reduced their afferent (dendritic spines) and efferent (mossy fiber terminals) connectivity. Finally, soluble Tau caused specific impairment of behavioral pattern separation capacity. Our results thus demonstrate for the first time that soluble Tau causes long-term detrimental effects on the morphology and connectivity of newborn granule neurons and that these effects correlate with impaired behavioral pattern separation skills. These data might be relevant for the field of neurodegenerative disorders, since they contribute to reinforcing the pathological roles played by distinct Tau species in vivo.Spanish Ministry of Economy and Competitiveness (SAF-2014-53040-P (to J.Á.) and RYC-2015-17189 (to M.LL.-M.)); the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain)Peer Reviewe

Prolonged fixation and post-mortem delay impede the study of adult neurogenesis in mice

Abstract Adult hippocampal neurogenesis (AHN) gives rise to new neurons throughout life. This phenomenon takes place in more than 120 mammalian species, including humans, yet its occurrence in the latter was questioned after one study proposed the putative absence of neurogenesis markers in the adult human hippocampus. In this regard, we showed that prolonged fixation impedes the visualization of Doublecortin+ immature neurons in this structure, whereas other authors have suggested that a dilated post-mortem delay (PMD) underlies these discrepancies. Nevertheless, the individual and/or additive contribution of fixation and the PMD to the detection (or lack thereof) of other AHN markers has not been studied to date. To address this pivotal question, we used a tightly controlled experimental design in mice, which allowed the dissection of the relative contribution of the aforementioned factors to the visualization of markers of individual AHN stages. Fixation time emerged as the most prominent factor globally impeding the study of this process in mice. Moreover, the visualization of other particularly sensitive epitopes was further prevented by prolonged PMD. These results are crucial to disambiguate current controversies related to the occurrence of AHN not only in humans but also in other mammalian species

Response to Comment on “Impact of neurodegenerative diseases on human adult hippocampal neurogenesis”

Alvarez-Buylla and colleagues provide an alternative interpretation of some of the data included in our manuscript and question whether well-validated markers of adult hippocampal neurogenesis (AHN) are related to this phenomenon in our study. In Terreros-Roncal et al., reconstruction of the main stages of human AHN revealed its enhanced vulnerability to neurodegeneration. Here, we clarify ambiguities raised by these authors.Fil: Terreros Roncal, J.. Universidad Autónoma de Madrid; EspañaFil: Moreno Jiménez, E. P.. Universidad Autónoma de Madrid; EspañaFil: Flor García, M.. Universidad Autónoma de Madrid; EspañaFil: Rodríguez Moreno, C. B.. Universidad Autónoma de Madrid; EspañaFil: Trinchero, Mariela Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Márquez Valadez, B.. Universidad Autónoma de Madrid; EspañaFil: Cafini, F.. Universidad Europea de Madrid;Fil: Rábano, A.. CIEN Foundation; EspañaFil: Llorens Martín, M.. Universidad Autónoma de Madrid; Españ