The hippocampus is one of the most affected areas in Alzheimer’s disease (AD)1. Moreover, this structure hosts one of the most unique phenomena of the adult mammalian brain, namely, the addition of new neurons throughout life2. This process, called adult hippocampal neurogenesis (AHN), confers an unparalleled degree of plasticity to the entire hippocampal circuitry3,4. 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.
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The data that support the findings of this study are available from the corresponding author upon reasonable request. All requests for raw and analyzed data will be promptly reviewed by the Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED) to determine whether the request is subject to any intellectual property or confidentiality obligations. Any materials that can be shared will be released via a material transfer agreement.
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The authors would like to thank the patients and their families for generously donating brain samples. Moreover, they would like to thank I. Rodal for help with human sample extraction and processing, E. García, R. Cuadros and the confocal microscopy facility of the CBMSO for technical assistance, and P. Moreno for help with illustration design. A number of human samples were generously provided by the Biobanco del Hospital Universitario Reina Sofia (Córdoba, Spain). The authors are grateful to R. Sánchez for providing some of these samples. They would also like to thank J. Gleeson (University of California, San Diego) for providing an anti-DCX antibody. This study was supported by the following: the Spanish Ministry of Economy and Competitiveness (SAF-2017-82185-R and RYC-2015-171899, M.L.-M.; SAF-2014-53040-P, J.Á.); the Alzheimer’s Association (2015-NIRG-340709 and AARG-17-528125, M.L.-M.); the Association for Frontotemporal Degeneration (2016 Basic Science Pilot Grant Award, M.L.-M.); the Comunidad de Madrid (PEJD-2017-PRE/BMD-3439, M.L.-M.); and the Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED, Spain, J.Á.). Institutional grants from the Fundación Ramón Areces and the Banco de Santander to CBMSO are also acknowledged. The salary of E.P.M.-J. was supported by a Comunidad de Madrid researcher contract (PEJD-2017-PRE/BMD-3439). The salary of J.T.-R. was supported by a Universidad Autónoma de Madrid doctoral fellowship (FPI-UAM 2017 program).
About this article
Nature Reviews Neuroscience (2019)