New neurons, old questions Cellular and molecular insights into the neurogenesis debate in Alzheimer’s disease

This thesis explores adult hippocampal neurogenesis (AHN) in the human brain, its relevance to Alzheimer’s disease (AD), and the regulatory role of microRNAs (miRNAs), particularly miR-132. While AHN is well-characterized in rodent models, its presence and function in the adult human brain remain controversial due to technical and conceptual limitations. In Part 1, we address these challenges using single-nuclei RNA sequencing (snRNA-seq) to identify neurogenic populations in human postmortem brain tissue. By refining experimental protocols and analytical pipelines, we provide evidence for a population of immature neurons in the hippocampus across healthy, AD-affected, and dementia-resilient individuals. Notably, these neurons show neuroprotective signatures in resilient individuals, suggesting a role in cognitive resilience.
Part 2 focuses on the role of miRNAs in regulating AHN and neuroinflammation. We review miRNA-mediated control of neural stem cell dynamics and demonstrate, through a multi-omics approach, that miR-132 regulates microglial activation and homeostasis. miR-132 dysregulation—consistently observed in AD—was shown to affect disease-associated microglial states in both mouse models and human iPSC-derived microglia.
Together, these findings advance our understanding of human AHN and its regulation, offering new insights into the cellular and molecular mechanisms underlying cognitive decline and resilience in AD. This work underscores the importance of refined methodological approaches and highlights miR-132 as a potential therapeutic target in neurodegenerative disease.