Giorgia Tosoni

Alzheimer’s disease (AD) is a progressive, irreversible disorder accounting for 50-70% of all dementia cases. Given the current lack of disease-modifying therapies, systematic profiling of the cell type- and cell state-specific molecular signatures of resilience and vulnerability to AD may reveal novel therapeutic avenues. Adult hippocampal neurogenesis (AHN) refers to the birth of new neurons in the neurogenic ‘niche’ of a hippocampal subregion, the dentate gyrus (DG). AHN drops sharply in AD, and positively correlates with ante-mortem cognition. Our work and previous reports show that boosting AHN in AD mice restores AHN-related memory. Hence, harnessing AHN in human AD brain may provide novel strategies to prevent or counteract dementia. Insights into the molecular and cellular regulatory networks maintaining homeostasis of the human neurogenic microenvironment are currently missing. Here, we employ single-nucleus RNA sequencing technology in the human AHN niche to profile cell type specific molecular signatures of AHN and their changes during the course of AD pathology and in resilient brains. We developed a novel protocol for precise microdissection of the AHN niche in tissue sections of postmortem human brain, which yields high-quality input material, enriched for niche-resident cell populations. We employ in silico ‘dissection’ of cellular populations putatively including neurogenic cell types, and lineage trajectories to identify any (rare) bona fide progenitors. Using previously published and our own datasets, we identify species-conserved and human-specific markers that could be used for more reliable identification of adult neurogenic populations and of their transcriptional alterations in AD and resilient brains. In addition, we probe a series of specific challenges that require particular attention and would greatly profit from an open discussion in the field.