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Project 01
Adult neurogenesis
in humans
ERC Consolidator Grant 2020, ERC-CoG-2020-101001916. “HumAN: Interrogating human adult hippocampal neurogenesis”
Further reading
Deepening our understanding on the mechanisms that drive the functional integration of new neurons in the human hippocampus is supported by the award of the ERC Consolidator Grant 2020 “HumAN: Interrogating human adult hippocampal neurogenesis” (ERC-CoG-2020-101001916).
Principal Investigator
María Llorens-Martín
Summary
HumAN is aimed at unveiling the features that confer neurogenic potential to the human hippocampus, thoroughly characterising this specialised niche in adulthood, physiological aging, and pathological conditions. By using post-mortem human brain tissue of the highest quality, bioinformatics, advanced microscopy and molecular techniques at the single-cell level, HumAN will deepen our understanding not only of the mechanisms that control the maturation and synaptic integration of newly generated cells in human beings, but also of the pathophysiology of neurodegenerative and psychiatric diseases, thereby facilitating the identification of potential therapeutic targets for these as yet incurable conditions.
Members of the team involved
María Llorens-Martín (Principal Investigator)
Alberto Rábano (Collaborator)
Berenice Márquez-Valadez
Carla Rodríguez-Moreno
Elena Moreno-Jiménez
Fabio Cafini (Collaborator)
Ana V. Prádanos-Senén
Marta Gallardo
Miguel Flor-García
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Participating Institutions
Spanish Research Council (CSIC) (Spain) (Host Institution)
Universidad Autónoma de Madrid (UAM) (Spain)
CIBERNED (Spain)
Fundación CIEN (Spain)
Stanley Medical Research Institute (SMRI) (USA)
Results Obtained
Publications
a
Impact of neurodegenerative diseases on human adult hippocampal neurogenesis.
Terreros-Roncal J, Moreno-Jiménez EP, Flor-García M, Rodríguez-Moreno CB, Trinchero MF, Cafini F, Rábano A, Llorens-Martín M. (2021).
Science
374(6571):1106-1113.
doi: 10.1126/science.abl5163.
Link →
Expand Abstract: 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.
b
Progression of Alzheimer's disease parallels unusual structural plasticity of human dentate granule cells.
Márquez-Valadez B, Rábano A, Llorens-Martín M. (2022).
Acta Neuropathologica Communications
Aug 29;10(1):125.
doi: 10.1186/s40478-022-01431-7.
Link →
Expand Abstract: Alzheimer´s disease (AD), the most common form of dementia in industrialized countries, severely targets the hippocampal formation in humans and mouse models of this condition. The adult hippocampus hosts the continuous addition of new dentate granule cells (DGCs) in numerous mammalian species, including humans. Although the morphology and positioning of DGCs within the granule cell layer (GCL) match their developmental origin in rodents, a similar correlation has not been reported in humans to date. Our data reveal that DGCs located in inner portions of the human GCL show shorter and less complex dendrites than those found in outer portions of this layer, which are presumably generated developmentally.
Moreover, in AD patients, DGCs show early morphological alterations that are further aggravated as the disease progresses. An aberrantly increased number of DGCs with several primary apical dendrites is the first morphological change detected in patients at Braak-Tau I/II stages. This alteration persists throughout AD progression and leads to generalized dendritic atrophy at late stages of the disease. Our data reveal the distinct vulnerability of several morphological characteristics of DGCs located in the inner and outer portions of the GCL to AD and support the notion that the malfunction of the hippocampus is related to cognitive impairments in patients with AD.
c
Unraveling human adult hippocampal neurogenesis.
Flor-García M, Terreros-Roncal J, Moreno-Jiménez EP, Ávila J, Rábano A, Llorens-Martín M. (2020).
Nature Protocols
15(2):668-693.
doi: 10.1038/s41596-019-0267-y.
Link →
Expand Abstract: Adult neurogenesis occurs in a few selected regions of the mammalian brain. One such region is the hippocampus, the so-called gateway to memory, where adult hippocampal neurogenesis (AHN) occurs. Here, we provide a comprehensive description of the methods used in our laboratory to unambiguously detect a population of immature neurons in the human hippocampus until the 10th decade of life. The criteria used to refine and develop the current protocol include obtaining post-mortem human samples of remarkable quality and under tightly controlled conditions for immunohistochemistry (IHC) studies, optimizing tissue processing and histological procedures, establishing criteria to reliably validate antibody signal and performing unbiased stereological cell counts.
Moreover, we provide a detailed description of the parameters that, in our view, should be reported in human AHN studies. The opposing results obtained by introducing slight variations in the methodological conditions should be considered by future studies that seek to increase our knowledge of this fascinating process.
By applying simple and inexpensive tissue pre-treatments, this protocol, which can be completed in 7 days, might be applicable to a variety of IHC studies performed on other tissues of human (or animal) origin.
d
Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer's disease.
Moreno-Jiménez EP, Flor-García M, Terreros-Roncal J, Rábano A, Cafini F, Pallas-Bazarra N, Ávila J, Llorens-Martín M. (2019)
Nature Medicine
25(4):554-560.
doi: 10.1038/s41591-019-0375-9.
Link →
Expand Abstract: The hippocampus is one of the most affected areas in Alzheimer's disease (AD). Moreover, this structure hosts one of the most unique phenomena of the adult mammalian brain, namely, the addition of new neurons throughout life. This process, called adult hippocampal neurogenesis (AHN), confers an unparalleled degree of plasticity to the entire hippocampal circuitry. Nonetheless, direct evidence of AHN in humans has remained elusive. Thus, determining whether new neurons are continuously incorporated into the human dentate gyrus (DG) during physiological and pathological aging is a crucial question with outstanding therapeutic potential. By combining human brain samples obtained under tightly controlled conditions and state-of-the-art tissue processing
methods, we identified thousands of immature neurons in the DG of neurologically healthy human subjects up to the ninth decade of life.
These neurons exhibited variable degrees of maturation along differentiation stages of AHN. In sharp contrast, the number and maturation of these neurons progressively declined as AD advanced. These results demonstrate the persistence of AHN during both physiological and pathological aging in humans and provide evidence for impaired neurogenesis as a potentially relevant mechanism underlying memory deficits in AD that might be amenable to novel therapeutic strategies.
Invited talks and conferences
María Llorens-Martín
Brain Conference. 24-25 February 2022. “Human adult neurogenesis and neurodegenerative diseases”.
Link →
María Llorens-Martín
PhD Advanced Course Stem Cell Technologies. Champalimaud Foundation. 8-12 November 2021. “Human adult hippocampal neurogenesis during physiological and pathological aging”.
Link →
María Llorens-Martín
Society for Neuroscience (SfN). 19-23 October 2019, Chicago (USA). “Human adult neurogenesis & neurodegenerative diseases”. Dual Perspectives session: ‘Does adult hippocampal neurogenesis occur in humans?’
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Press
El País
21 Oct. 2021 “Demostrada la existencia de células madre en el cerebro que permiten la generación de neuronas durante toda la vida”
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TVE
Telediario de las 21:00 - 21 Oct 2021
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Centro de Biología Molecular Severo Ochoa (CBMSO) Universidad Autónoma de Madrid (Campus de Cantoblanco)
C/ Nicolás Cabrera 1 - 28049 Madrid (Spain)
María Llorens-Martín (PI)
m.llorens@csic.es
+34 911964632