Salta Group

Salta Group

Neurogenesis and Neurodegeneration

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Adult neurogenesis, human after all (again): Classic, optimized, and future approaches

Published in Behavioural Brain Research, 2020

In this perspective article, we reflect on the recent debate about the existence of human neurogenesis and discuss direct, and also indirect, support for the ongoing formation, and functional relevance, of new neurons in the adult and aged human hippocampus. To explain the discrepancies between several prominently published human studies, we discuss critical methodological aspects and highlight the importance of optimal tissue preservation and processing for histological examination. We further discuss novel approaches, like single-cell/nucleus sequencing and magnetic resonance spectroscopy, that will help advance the study of human neurogenesis to its fullest potential - understanding its contribution to human hippocampal functions and related disorders like depression and dementia.

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Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer’s Disease

Published in Cell, 2020

Although complex inflammatory-like alterations are observed around the amyloid plaques of Alzheimer’s disease (AD), little is known about the molecular changes and cellular interactions that characterize this response. We investigate here, in an AD mouse model, the transcriptional changes occurring in tissue domains in a 100-μm diameter around amyloid plaques using spatial transcriptomics. We demonstrate early alterations in a gene co-expression network enriched for myelin and oligodendrocyte genes (OLIGs), whereas a multicellular gene co-expression network of plaque-induced genes (PIGs) involving the complement system, oxidative stress, lysosomes, and inflammation is prominent in the later phase of the disease. We confirm the majority of the observed alterations at the cellular level using in situ sequencing on mouse and human brain sections. Genome-wide spatial transcriptomics analysis provides an unprecedented approach to untangle the dysregulated cellular network in the vicinity of pathogenic hallmarks of AD and other brain diseases.

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Restoring miR-132 expression rescues adult hippocampal neurogenesis and memory deficits in Alzheimer’s disease

Published in Cell Stem Cell, 2021

Neural stem cells residing in the hippocampal neurogenic niche sustain lifelong neurogenesis in the adult brain. Adult hippocampal neurogenesis (AHN) is functionally linked to mnemonic and cognitive plasticity in humans and rodents. In Alzheimer’s disease (AD), the process of generating new neurons at the hippocampal neurogenic niche is impeded, yet the mechanisms involved are unknown. Here we identify miR-132, one of the most consistently downregulated microRNAs in AD, as a potent regulator of AHN, exerting cell-autonomous proneurogenic effects in adult neural stem cells and their progeny. Using distinct AD mouse models, cultured human primary and established neural stem cells, and human patient material, we demonstrate that AHN is directly affected by AD pathology. miR-132 replacement in adult mouse AD hippocampus restores AHN and relevant memory deficits. Our findings corroborate the significance of AHN in mouse models of AD and reveal the possible therapeutic potential of targeting miR-132 in neurodegeneration.

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The promise of microRNA-based therapies in Alzheimer’s disease: challenges and perspectives

Published in Molecular Neurodegeneration, 2021

Multi-pathway approaches for the treatment of complex polygenic disorders are emerging as alternatives to classical monotarget therapies and microRNAs are of particular interest in that regard. MicroRNA research has come a long way from their initial discovery to the cumulative appreciation of their regulatory potential in healthy and diseased brain. However, systematic interrogation of putative therapeutic or toxic effects of microRNAs in (models of) Alzheimer’s disease is currently missing and fundamental research findings are yet to be translated into clinical applications. Here, we review the literature to summarize the knowledge on microRNA regulation in Alzheimers pathophysiology and to critically discuss whether and to what extent these increasing insights can be exploited for the development of microRNA-based therapeutics in the clinic.

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Hippocampal neuropathology in suicide: Gaps in our knowledge and opportunities for a breakthrough

Published in Neuroscience & Biobehavioral Reviews, 2022

Suicide is a major global hazard. There is a need for increasing suicide awareness and effective and evidence-based interventions, targeting both suicidal ideation and conduct. However, anti-suicide pharmacological effects are unsatisfactory. The human hippocampus is vulnerable to neuropsychiatric damages and subsequently releases psychobiological signals. Human hippocampal studies of suicide completers have shown mechanistic changes in neurobiology, which, however, could not reflect the neuropathological fingerprints of fatal suicide ideations and suicide attempts. In this review, we provide several leading theories of suicide, including the serotoninergic system, Wnt pathway and brain-derived neurotrophic factor/tropomyosin receptor kinase B signalling, and discuss the evidence for their roles in suicide and treatment. Moreover, the cognitive dysfunctions associated with suicide risk are discussed, as well as the novel evidence on cognitive therapies that decrease suicidal ideation. We highlight the need to apply multi-omics techniques (including single-nucleus RNA sequencing and mass spectrometry histochemistry) on hippocampal samples from donors who died by suicide or legal euthanasia, to clarify the aetiology of suicide and propose novel therapeutic strategies.

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Adult Neural Stem Cell Regulation by Small Non-coding RNAs: Physiological Significance and Pathological Implications

Published in Frontiers in Cellular Neuroscience, 2022

The adult neurogenic niches are complex multicellular systems, receiving regulatory input from a multitude of intracellular, juxtacrine, and paracrine signals and biological pathways. Within the niches, adult neural stem cells (aNSCs) generate astrocytic and neuronal progeny, with the latter predominating in physiological conditions. The new neurons generated from this neurogenic process are functionally linked to memory, cognition, and mood regulation, while much less is known about the functional contribution of aNSC-derived newborn astrocytes and adult-born oligodendrocytes. Accumulating evidence suggests that the deregulation of aNSCs and their progeny can impact, or can be impacted by, aging and several brain pathologies, including neurodevelopmental and mood disorders, neurodegenerative diseases, and also by insults, such as epileptic seizures, stroke, or traumatic brain injury. Hence, understanding the regulatory underpinnings of aNSC activation, differentiation, and fate commitment could help identify novel therapeutic avenues for a series of pathological conditions. Over the last two decades, small non-coding RNAs (sncRNAs) have emerged as key regulators of NSC fate determination in the adult neurogenic niches. In this review, we synthesize prior knowledge on how sncRNAs, such as microRNAs (miRNAs) and piwi-interacting RNAs (piRNAs), may impact NSC fate determination in the adult brain and we critically assess the functional significance of these events. We discuss the concepts that emerge from these examples and how they could be used to provide a framework for considering aNSC (de)regulation in the pathogenesis and treatment of neurological diseases.

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Adult hippocampal neurogenesis in Alzheimer’s disease: A roadmap to clinical relevance

Published in Cell Stem Cell, 2023

Adult hippocampal neurogenesis (AHN) drops sharply during early stages of Alzheimer’s disease (AD), via unknown mechanisms, and correlates with cognitive status in AD patients. Understanding AHN regulation in AD could provide a framework for innovative pharmacological interventions. We here combine molecular, behavioral, and clinical data and critically discuss the multicellular complexity of the AHN niche in relation to AD pathophysiology. We further present a roadmap toward a better understanding of the role of AHN in AD by probing the promises and caveats of the latest technological advancements in the field and addressing the conceptual and methodological challenges ahead.

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Mapping human adult hippocampal neurogenesis with single-cell transcriptomics: Reconciling controversy or fueling the debate?

Published in Neuron, 2023

The notion of exploiting the regenerative potential of the human brain in physiological aging or neurological diseases represents a particularly attractive alternative to conventional strategies for enhancing or restoring brain function. However, a major first question to address is whether the human brain does possess the ability to regenerate. The existence of human adult hippocampal neurogenesis (AHN) has been at the center of a fierce scientific debate for many years. The advent of single-cell transcriptomic technologies was initially viewed as a panacea to resolving this controversy. However, recent single-cell RNA sequencing studies in the human hippocampus yielded conflicting results. Here, we critically discuss and re-analyze previously published AHN-related single-cell transcriptomic datasets. We argue that, although promising, the single-cell transcriptomic profiling of AHN in the human brain can be confounded by methodological, conceptual, and biological factors that need to be consistently addressed across studies and openly discussed within the scientific community.

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Predicting progression to Alzheimer’s disease with human hippocampal progenitors exposed to serum

Published in Brain, 2023

Adult hippocampal neurogenesis is important for learning and memory and is altered early in Alzheimer’s disease. As hippocampal neurogenesis is modulated by the circulatory systemic environment, evaluating a proxy of how hippocampal neurogenesis is affected by the systemic milieu could serve as an early biomarker for Alzheimer’s disease progression. Here, we used an in vitro assay to model the impact of systemic environment on hippocampal neurogenesis. A human hippocampal progenitor cell line was treated with longitudinal serum samples from individuals with mild cognitive impairment, who either progressed to Alzheimer’s disease or remained cognitively stable. Mild cognitive impairment to Alzheimer’s disease progression was characterized most prominently with decreased proliferation, increased cell death and increased neurogenesis. A subset of baseline cellular readouts together with education level were able to predict Alzheimer’s disease progression. The assay could provide a powerful platform for early prognosis, monitoring disease progression and further mechanistic studies.

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microRNA-132 regulates gene expression programs involved in microglial homeostasis

Published in iScience, 2023

microRNA-132 (miR-132), a known neuronal regulator, is one of the most robustly downregulated microRNAs (miRNAs) in the brain of Alzheimer’s disease (AD) patients. Increasing miR-132 in AD mouse brain ameliorates amyloid and Tau pathologies, and also restores adult hippocampal neurogenesis and memory deficits. However, the functional pleiotropy of miRNAs requires in-depth analysis of the effects of miR-132 supplementation before it can be moved forward for AD therapy. We employ here miR-132 loss- and gain-of-function approaches using single-cell transcriptomics, proteomics, and in silico AGO-CLIP datasets to identify molecular pathways targeted by miR-132 in mouse hippocampus. We find that miR-132 modulation significantly affects the transition of microglia from a disease-associated to a homeostatic cell state. We confirm the regulatory role of miR-132 in shifting microglial cell states using human microglial cultures derived from induced pluripotent stem cells.

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MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer’s disease

Published in Science, 2023

Neuronal cell loss is a defining feature of Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. We xenografted human or mouse neurons into the brain of a mouse model of AD. Only human neurons displayed tangles, Gallyas silver staining, granulovacuolar neurodegeneration (GVD), phosphorylated tau blood biomarkers, and considerable neuronal cell loss. The long noncoding RNA MEG3 was strongly up-regulated in human neurons. This neuron-specific long noncoding RNA is also up-regulated in AD patients. MEG3 expression alone was sufficient to induce necroptosis in human neurons in vitro. Down-regulation of MEG3 and inhibition of necroptosis using pharmacological or genetic manipulation of receptor-interacting protein kinase 1 (RIPK1), RIPK3, or mixed lineage kinase domain-like protein (MLKL) rescued neuronal cell loss in xenografted human neurons. This model suggests potential therapeutic approaches for AD and reveals a human-specific vulnerability to AD.

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NACC2, a molecular effector of miR-132 regulation at the interface between adult neurogenesis and Alzheimer’s disease

Published in Scientific Reports, 2024

The generation of new neurons at the hippocampal neurogenic niche, known as adult hippocampal neurogenesis (AHN), and its impairment, have been implicated in Alzheimer’s disease (AD). MicroRNA-132 (miR-132), the most consistently downregulated microRNA (miRNA) in AD, was recently identified as a potent regulator of AHN, exerting multilayered proneurogenic effects in adult neural stem cells (NSCs) and their progeny. Supplementing miR-132 in AD mouse brain restores AHN and relevant memory deficits, yet the exact mechanisms involved are still unknown. Here, we identify NACC2 as a novel miR-132 target implicated in both AHN and AD. miR-132 deficiency in mouse hippocampus induces Nacc2 expression and inflammatory signaling in adult NSCs. We show that miR-132-dependent regulation of NACC2 is involved in the initial stages of human NSC differentiation towards astrocytes and neurons. Later, NACC2 function in astrocytic maturation becomes uncoupled from miR-132. We demonstrate that NACC2 is present in reactive astrocytes surrounding amyloid plaques in mouse and human AD hippocampus, and that there is an anticorrelation between miR-132 and NACC2 levels in AD and upon induction of inflammation. Unraveling the molecular mechanisms by which miR-132 regulates neurogenesis and cellular reactivity in AD, will provide valuable insights towards its possible application as a therapeutic target.

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Cross-Analysis of Single-Cell Transcriptomic Datasets Reveals Conserved Neurogenic Gene Signatures and New Insights Into Neural Stem Cell Aging

Published in Aging Cell, 2025

Hippocampal adult neural stem cells (NSCs) contribute to neurogenesis and astrogliogenesis throughout life. They play multifaceted roles in hippocampal function, including memory processing, stress regulation, and cognitive flexibility. Located in unique neurogenic niches like the subgranular zone of the hippocampal dentate gyrus, NSCs exhibit notable heterogeneity and can be classified into quiescent, activated, and intermediate transitioning states. This diversity, while instrumental to their adaptability and function, presents challenges in molecular classification and functional interrogation. Here, we discuss current limitations and compare NSC transcriptional profiles from publicly available single-cell RNA sequencing datasets. We address discrepancies in NSC classification between studies, identify conserved gene expression profiles, and propose new markers that could serve as standardized references. Furthermore, we explore how pseudotime inference analyses provide insights into the temporal dynamics of NSCs and their progression toward neural progenitors, further aiming to optimize their classification. We also examine cellular changes in NSCs during aging and explore the potential of these cells to undergo senescence. Our work helps to resolve inconsistencies in current cell-type annotations in literature and proposes a framework to study and classify the different states of NSCs, thereby offering a better understanding of their dynamic roles in neurogenesis, aging, and cellular senescence.

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Mind, mood and new neurons: Probing adult hippocampal neurogenesis in neuropsychiatry and beyond

Published in Cell Stem Cell, 2025

In this issue of Cell Stem Cell, Márquez-Valadez, Gallardo-Caballero, and Llorens-Martín report that adult hippocampal neurogenesis (AHN) is differentially disrupted in neuropsychiatric disorders. Their findings highlight the role of the neurogenic niche and lifestyle, supporting the view of human AHN as a dynamic process sensitive to biology and behavior.

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Inhibition of stress resilience and adult hippocampal neurogenesis by platelet-derived LPA16:0 in anxiety

Published in Nature Communications, 2026

Anxiety is an aggravating comorbidity of many psychiatric disorders that is often underdiagnosed and undertreated, and little is known on the mechanisms underlying its regulation. Here, we find that serum LPA16:0 abundance increases with trait anxiety in both humans and mice; while high LPA16:0 levels are sufficient to reduce the in vitro proliferation of adult hippocampal neural stem/progenitor cells. In humans, the main LPA receptor LPA1, bears single nucleotide polymorphism variants associated with anxiety. In mice, LPA16:0 decreases hippocampal neurogenesis and stress resilience, whereas LPA1 antagonism or the reduction of platelets, the main source of circulating LPA16:0, increases adult neurogenesis and resilience to acute stress. Conditional knockdown of LPA₁ receptor in neural stem cells is sufficient to enhance cell proliferation in the dentate gyrus. Finally, the inhibition of adult neurogenesis abolishes the beneficial effect of LPA1 antagonism on resilience against both acute and chronic stress. Together, these findings identify circulating LPA16:0 as a biomarker of trait anxiety and LPA16:0-LPA1 signaling as a regulation mechanism of mood-related behavior through the decrease of adult neurogenesis.

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Adult neurogenesis: New neurons, new opportunities

Published in Cell Stem Cell, 2026

The 38 currently registered clinical trials with the keyword ‘adult neurogenesis’ indicate growing interest in new neurons as a target for intervention. Today, we have strong evidence that adult neurogenesis is involved in hippocampal function and can contribute to brain functions in health and disease. Neurogenesis research can now ask new questions, such as (1) the identity of stem cells and their input integration for initiating neurogenesis, (2) the nature of the neurogenic niche and neurogenesis without stem cell activity, (3) the complex functionality beyond the hippocampus, and (4) evolutionary and computational theory, including neurogenic neural networks for artificial intelligence.

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microRNA-132 attenuates inflammation in induced pluripotent stem cell-derived microglia from Alzheimer’s disease patients

Published in Acta Neuropathologica Communications, 2026

Microglia, the resident immune cells of the brain, are increasingly recognized as key contributors to Alzheimer’s disease (AD) pathology. Multiple studies have identified microRNA-132 (miR-132) as one of the most significantly downregulated microRNAs in AD. Apart from well-established pleiotropic regulatory functions in neurons, previous evidence also suggested a role for miR-132 in regulating (neuro)inflammation. Yet, the precise mechanisms by which miR-132 impacts microglia remain unknown. In this study, we investigated the role of miR-132 in modulating microglial gene expression and function using gain- and loss-of-function approaches in human-induced pluripotent stem cell (iPSC)-derived microglia (iMGs) from both healthy controls and sporadic AD (sAD) patients. Our findings indicate that while miR-132 may not be indispensable for some baseline microglial functions, increasing its expression in sAD iMGs can reverse disease-associated gene expression changes and attenuate inflammatory responses. To further explore its therapeutic potential, we overexpressed miR-132 in hippocampal neurons of an AD mouse model, employing a clinically relevant adeno-associated viral (AAV) delivery method. miR-132 overexpression was well-tolerated and induced non-cell autonomous effects in microglia. This study sheds light into the regulatory role of miR-132 in microglia under both physiological and AD conditions, and emphasizes the importance of optimizing safe dosage parameters for future clinical applications.

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Transcriptional profiles of immature neurons in aged human hippocampus track Alzheimer’s pathology and cognitive resilience

Published in Cell Stem Cell, 2026

The existence and functional significance of immature neurons in the adult human brain, particularly in the context of neurodegenerative disorders, remain an open question. Although rodent studies have highlighted active roles for adult-born immature neurons in the hippocampus both under healthy conditions and in Alzheimer’s disease (AD), evidence from the human brain is limited and lacks detailed molecular characterization. To address this gap, we performed single-nucleus RNA sequencing in aged healthy, AD, and dementia-resilient human hippocampus samples to probe immature neuronal signatures and gene expression alterations associated with AD pathology and resilience. By applying an integrated experimental and computational pipeline, we identified persistent populations of immature neurons across all donor groups, with transcriptional profiles reflecting ‘juvenile’ cellular functions, which are compromised in AD. Our findings suggest that the presence of these immature neuronal populations per se may actively contribute to maintaining homeostasis within the aged human hippocampus and to cognitive resilience in AD.

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teaching

Teaching experience 1

Undergraduate course, University 1, Department, 2014

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Teaching experience 2

Workshop, University 1, Department, 2015

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