Interrogating Human Adult Hippocampal Neurogenesis

Project Information

HumAN

Grant agreement ID: 101001916

DOI

10.3030/101001916

EC signature date 22 July 2021

Start date 1 October 2021

End date 30 September 2026

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 993 792,74

EU contribution

€ 1 993 792,74

Coordinated by

AGENCIA ESTATAL CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS
Spain

Periodic Reporting for period 2 - HumAN (Interrogating Human Adult Hippocampal Neurogenesis)

Reporting period: 2023-04-01 to 2024-09-30

Summary of the context and overall objectives of the project

The hippocampus is a region of the mammalian brain that participates in learning and memory. Moreover, new neurons are generated in this structure throughout life in a process named adult hippocampal neurogenesis (AHN). Recent work by my group has revealed the persistence of AHN until the tenth decade of human life and the impairment of this process in patients with neurodegenerative diseases. Newly generated neurons are surrounded by a specialized and protective environment, which is damaged during aging and disease. Consequently, impaired AHN might lead to cognitive dysfunction and mood dysregulation. The general aim of HumAN is to unveil the features that allow the generation of new neurons in the human hippocampus. Specifically, we will thoroughly characterize this process during physiological aging and in patients with distinct disorders. To this end, we will use human brain samples of the highest quality possible, artificial intelligence, and advanced microscopy techniques. HumAN will further our understanding not only of the mechanisms that regulate the generation of new neurons in the human brain but also of the pathophysiology of neurodegenerative and psychiatric diseases, thereby facilitating the identification of potential novel therapeutic targets for these as-yet incurable conditions.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Our initial work has unveiled the presence of cells that have allowed the reconstruction of the whole adult hippocampal neurogenesis (AHN) process in humans. These cells include neural stem cells (NSCs) (the cells that divide and give rise to neurons), cells that undergoing cell division and maturation, and neurons at distinct stages of maturity. Moreover, we showed that AHN is damaged in patients with distinct neurodegenerative diseases (namely Alzheimer´s disease, Parkinson´s disease, Huntington´s disease, Amyotrophic Lateral Sclerosis, Lewy body dementia, and Frontotemporal dementia). In patients with Alzheimer´s disease, hippocampal neurons show an aberrant morphology that is likely to impede adequate connections with other cells. A similar morphology was observed in the same cells in patients with other neurodegenerative diseases such as Frontotemporal dementia. One of the most striking results observed is that AHN is altered in a very particular way in each of the diseases we have studied. For instance, patients with Amyotrophic Lateral Sclerosis have higher numbers of NSCss, whereas those with other disorders do not show this alteration. Immature neurons are altered, in a variable manner, in all the diseases addressed. For instance, in patients with Huntington´s disease, immature neurons remain at very immature stages, whereas in those with Parkinson´s disease, the most remarkable alterations in these cells appear when they have reached more advanced stages of maturity. The differential alterations observed in each disorder have driven the hypothesis that each neurodegenerative condition triggers the appearance of a unique combination of alterations in AHN, which we refer to as a particular adult hippocampal neurogenesis signature. Moreover, in all the diseases examined, the cells that accompany the newly generated neurons throughout their life (what is called the adult neurogenic niche) show dramatic alterations that point to neuroinflammation as a common factor of most neurodegenerative disorders and aging. All these findings were published (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. SCIENCE. 2021 Nov 26;374(6571):1106-1113. PMID: 34672693). We are currently studying adult hippocampal alterations in patients with psychiatric disorders.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Through HumAN, we have demonstrated the presence of neural stem cells in the adult human dentate gyrus—a long-debated question in modern neuroscience. Moreover, our exhaustive analyses have revealed that distinct neurodegenerative diseases cause different alterations in adult hippocampal neurogenesis. These findings might be relevant to our understanding of the pathological processes that occur in the brains of patients with each of these disorders. The high quality of our human brain samples, together with the sophisticated processing of these samples done in our lab, has allowed these pioneering analyses of the human hippocampal neurogenic niche in patients with distinct pathologies, as well as in healthy aged subjects. These results have been published in an impactful article (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. SCIENCE. 2021 Nov 26;374(6571):1106-1113. PMID: 34672693).
In the coming months, we will address the impairments in adult hippocampal neurogenesis present in patients with psychiatric disorders. Moreover, we are currently developing sophisticated tools to address, at the single-cell level, the molecular alterations that drive these alterations.

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