Molecular Diversity Among Adult Human Hippocampal and Entorhinal Cells

Franjic, Daniel; Choi, Jinmyung; Škarica, Mario; Xu, Chuan; Li, Qian; Ma, Shaojie; Tebbenkamp, Andrew T.N.; Santpere, Gabriel; Arellano, Jon I.; Gudelj, Ivan; Jankovic-Rapan, Lucija; Sousa, André M. M.; Rakić, Paško; Šestan, Nenad

doi:10.1101/2019.12.31.889139

Cited by 16 publications

(13 citation statements)

References 126 publications

(192 reference statements)

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“…4 ). This similarity is consistent with the reported similarity between deep layer neocortical excitatory neurons and EC excitatory neurons in general 28 . The similarity in transcriptomes of vulnerable excitatory neurons in different brain regions is intriguing and suggests similar mechanisms of selective vulnerability in different brain regions.…”

Section: Resultssupporting

confidence: 92%

Molecular characterization of selectively vulnerable neurons in Alzheimer’s disease

et al. 2021

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Alzheimer’s disease (AD) is characterized by the selective vulnerability of specific neuronal populations, the molecular signatures of which are largely unknown. To identify and characterize selectively vulnerable neuronal populations, we used single-nucleus RNA sequencing to profile the caudal entorhinal cortex and the superior frontal gyrus – brain regions where neurofibrillary inclusions and neuronal loss occur early and late in AD, respectively – from postmortem brains spanning the progression of AD-type tau neurofibrillary pathology. We identified RORB as a marker of selectively vulnerable excitatory neurons in the entorhinal cortex, and subsequently validated their depletion and selective susceptibility to neurofibrillary inclusions during disease progression using quantitative neuropathological methods. We also discovered an astrocyte subpopulation, likely representing reactive astrocytes, characterized by decreased expression of genes involved in homeostatic functions. Our characterization of selectively vulnerable neurons in AD paves the way for future mechanistic studies of selective vulnerability and potential therapeutic strategies for enhancing neuronal resilience.

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Section: Resultssupporting

confidence: 92%

Molecular characterization of selectively vulnerable neurons in Alzheimer’s disease

et al. 2021

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“…2e). This finding is consistent with the reported similarity between deep layer neocortical excitatory neurons and EC excitatory neurons in general 41 . Furthermore, this correspondence was preserved when we mapped subpopulations in the EC to those in the SFG by performing cross-sample alignment for both brain regions jointly (Extended Data Fig.…”

Section: Selective Vulnerability Of Excitatory Neuron Subpopulationssupporting

confidence: 93%

Molecular characterization of selectively vulnerable neurons in Alzheimer’s Disease

Leng

Eser

et al. 2020

Preprint

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Alzheimer's disease (AD) is characterized by the selective vulnerability of specific neuronal populations, the molecular signatures of which are largely unknown. To identify and characterize selectively vulnerable neuronal populations, we used single-nucleus RNA sequencing to profile the caudal entorhinal cortex and the superior frontal gyrus -brain regions where neurofibrillary inclusions and neuronal loss occur early and late in AD, respectively -from individuals spanning the neuropathological progression of AD. We identified RORB as a marker of selectively vulnerable excitatory neurons in the entorhinal cortex, and subsequently validated their depletion and selective susceptibility to neurofibrillary inclusions during disease progression using quantitative neuropathological methods. We also discovered an astrocyte subpopulation, likely representing reactive astrocytes, characterized by decreased expression of genes involved in homeostatic functions. Our characterization of selectively vulnerable neurons in AD paves the way for future mechanistic studies of selective vulnerability and potential therapeutic strategies for enhancing neuronal resilience. MAIN TEXTSelective vulnerability is a fundamental feature of neurodegenerative diseases, in which different neuronal populations show a gradient of susceptibility to degeneration 1, 2 . Selective vulnerability at the network level has been extensively explored in Alzheimer's disease (AD) 3-5 , currently the leading cause of dementia and lacking in effective therapies. However, little is known about the mechanisms underlying selective vulnerability at the cellular level in AD, which could provide insight into disease mechanisms and lead to therapeutic strategies.The entorhinal cortex (EC), an allocortex, is one of the first cortical brain regions to exhibit neuronal loss in AD 6 . Neurons in the external EC layers, especially in layer II (also known as alpha clusters of the lamina principalis externa, abbreviated "Pre-alpha") 7 , accumulate taupositive neurofibrillary changes and die early on in the course of AD 8-13 . However, these selectively vulnerable neurons have yet to be characterized extensively at the molecular level. Furthermore, it is unknown whether there are differences in vulnerability among subpopulations of these neurons. Although rodent models of AD have offered some insights [14][15][16] , the human brain has unique features with regard to cellular physiology, composition and aging [17][18][19] , limiting the extrapoloation of findings from animal models to address selective vulnerability.Previous studies have combined laser capture microdissection with microarray analysis of gene expression 20, 21 to characterize EC neurons in AD, but focused on disease-related changes in gene expression, rather than selective vulnerability. More recently, single-nucleus RNA-sequencing (snRNA-seq) has enabled large-scale characterization of transcriptomic profiles of individual cells from post-mortem human brain tissue 22, 23 . However, snRNA-seq studies of AD p...

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“…(Verwer et al, 2007). More recently, non-neuronal expression of DCX has been corroborated using single-cell sequencing (Franjic et al, 2021). Thus, DCX 1 cells that are not costained with specific neuron markers might be glial cells.…”

Section: Labels More Than Just Newborn Neuronsmentioning

confidence: 97%

Positive Controls in Adults and Children Support That Very Few, If Any, New Neurons Are Born in the Adult Human Hippocampus

et al. 2021

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Adult hippocampal neurogenesis was originally discovered in rodents. Subsequent studies identified the adult neural stem cells and found important links between adult neurogenesis and plasticity, behavior, and disease. However, whether new neurons are produced in the human dentate gyrus (DG) during healthy aging is still debated. We and others readily observe proliferating neural progenitors in the infant hippocampus near immature cells expressing doublecortin (DCX), but the number of such cells decreases in children and few, if any, are present in adults. Recent investigations using dual antigen retrieval find many cells stained by DCX antibodies in adult human DG. This has been interpreted as evidence for high rates of adult neurogenesis, even at older ages. However, most of these DCX-labeled cells have mature morphology. Furthermore, studies in the adult human DG have not found a germinal region containing dividing progenitor cells. In this Dual Perspectives article, we show that dual antigen retrieval is not required for the detection of DCX in multiple human brain regions of infants or adults. We review prior studies and present new data showing that DCX is not uniquely expressed by newly born neurons: DCX is present in adult amygdala, entorhinal and parahippocampal cortex neurons despite being absent in the neighboring DG. Analysis of available RNA-sequencing datasets supports the view that DG neurogenesis is rare or absent in the adult human brain. To resolve the conflicting interpretations in humans, it is necessary to identify and visualize dividing neuronal precursors or develop new methods to evaluate the age of a neuron at the single-cell level.

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Molecular Diversity Among Adult Human Hippocampal and Entorhinal Cells

Cited by 16 publications

References 126 publications

Molecular characterization of selectively vulnerable neurons in Alzheimer’s disease

Molecular characterization of selectively vulnerable neurons in Alzheimer’s disease

Molecular characterization of selectively vulnerable neurons in Alzheimer’s Disease

Positive Controls in Adults and Children Support That Very Few, If Any, New Neurons Are Born in the Adult Human Hippocampus

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