More Confirming Data for Adult Human Neurogenesis
That new neurons are generated in the adult brain and integrate into existing neural networks was first established in mice in the 1990s, but considerable debate has taken place since then as to whether this adult neurogenesis also occurs in humans. Working with human brain tissue has always been logistically difficult, and this combined with methological challenges in the quantification of neurogenesis allowed uncertainty to continue. At this point, the balance of evidence and scientific consensus is that adult neurogenesis does occur in our species, and further is necessary to the operation of memory and learning. Here, in addition to providing further confirming data for human adult neurogenesis, researchers suggest that differences in neurogenesis could contribute to sustained cognitive function in older individuals who exhibit relatively little cognitive aging.
The existence of human hippocampal neurogenesis has long been disputed and its relevance in cognition remains unknown. Recent studies have established the presence of proliferating progenitors and immature neurons and a reduction in the latter in Alzheimer's disease (AD). However, their origin and the molecular networks that regulate neurogenesis and function are poorly understood. Here we studied human post-mortem hippocampi obtained from different cohorts: young adults with intact memory, aged adults with no cognitive impairments, aged adults with extraordinary memory capacity (SuperAgers), adults with preclinical intermediate pathology or adults with AD.
Using multiomic single-cell sequencing (single-nucleus RNA sequencing and single-nuclei assay for transposase-accessible chromatin with sequencing), we analysed the profiles of 355,997 nuclei isolated from the hippocampus samples and identified neural stem cells, neuroblasts and immature granule neurons.
Dysregulated neurogenesis was largely associated with changes in chromatin accessibility. Analyses of transcription factors and target gene signatures that distinguished each of the groups revealed early alterations in chromatin accessibility of neurogenic cells from individuals with preclinical AD, and such changes were even more evident in samples from individuals with AD. We identified a distinct profile of neurogenesis in SuperAgers that may reflect a 'resilience signature'. Finally, alterations in the profile of astrocytes and CA1 neurons govern cognitive function in the ageing hippocampus. Together, our study points to a multiomic molecular signature of the hippocampus that distinguishes cognitive resilience and deterioration with ageing.