Multicellular communities are perturbed in the aging human brain and Alzheimer’s disease

Cain, Anael; Taga, Mariko; McCabe, Cristin; Green, Gilad S.; Hekselman, Idan; White, Charles C.; Lee, Dylan I.; Gaur, Pallavi; Rozenblatt-Rosen, Orit; Zhang, Feng; Yeger-Lotem, Esti; Bennett, David A.; Yang, Hyun‐Sik; Regev, Aviv; Menon, Vilas

doi:10.1038/s41593-023-01356-x

Cited by 43 publications

(25 citation statements)

References 62 publications

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“…Our key analysis was to associate differences in subpopulation composition within each major cell type with specific AD phenotypes. We selected neurofibrillary tangle (NFT) spread as the AD phenotype of interest because of its stereotyped progression and its strong association with cognitive decline 3,12 . In particular, we used the Braak staging paradigm, which assigns a stage (from 1 to 6) based on the overall spread of tau pathology in an individual, with early stages (Braak 1/2) indicating NFT accumulation primarily in the entorhinal cortex and hippocampus, and later stages (Braak 3/4/5/6) describing individuals with tau pathology in both early and late-affected (cortical) regions.…”

Section: Resultsmentioning

confidence: 99%

“…To further expand our analysis of transcriptomic signatures within the TC, we incorporated data from five previously published studies, including 888,784 total nuclei (Table1). This comprehensive analysis with different brain regions such as the entorhinal cortex 10,11 , prefrontal cortex 12,13,5 , and superior frontal gyrus 10 allowed us to replicate a subset of the cell type associations. Finally, we explored the spatial distribution of a subset of key cell type-specific genes in 13 individuals through the CARTANA targeted in-situ sequencing (ISS) platform 14 (Fig.1a).…”

Section: Mainmentioning

confidence: 99%

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Single-nucleus and spatial transcriptomic profiling of human temporal cortex and white matter reveals novel associations with AD pathology

Gaur,

Bryois,

Calini

et al. 2024

Preprint

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Alzheimer's disease (AD) is a neurodegenerative disorder with complex pathological manifestations and is the leading cause of cognitive decline and dementia in elderly individuals. A major goal in AD research is to identify new therapeutic pathways by studying the molecular and cellular changes in the disease, either downstream or upstream of the pathological hallmarks. In this study, we present a comprehensive investigation of cellular heterogeneity from the temporal cortex region of 40 individuals, comprising healthy donors and individuals with differing tau and amyloid burden. Using single-nucleus transcriptome analysis of 430,271 nuclei from both gray and white matter of these individuals, we identified cell type-specific subclusters in both neuronal and glial cell types with varying degrees of association with AD pathology. In particular, these associations are present in layer specific glutamatergic (excitatory) neuronal types, along with GABAergic (inhibitory) neurons and glial subtypes. These associations were observed in early as well as late pathological progression. We extended this analysis by performing multiplexed in situ hybridization using the CARTANA platform, capturing 155 genes in 13 individuals with varying levels of tau pathology. By modeling the spatial distribution of these genes and their associations with the pathology, we not only replicated key findings from our snRNA data analysis, but also identified a set of cell type-specific genes that show selective enrichment or depletion near pathological inclusions. Together, our findings allow us to prioritize specific cell types and pathways for targeted interventions at various stages of pathological progression in AD.

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Section: Resultsmentioning

confidence: 99%

Section: Mainmentioning

confidence: 99%

Single-nucleus and spatial transcriptomic profiling of human temporal cortex and white matter reveals novel associations with AD pathology

Gaur,

Bryois,

Calini

et al. 2024

Preprint

Self Cite

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“…Whereas this observation is intriguing in understanding how demyelinating diseases could affect cortical grey matter, further examination of selective neuronal vulnerability is warranted. Indeed, the lack of strong differential neuronal signals may indicate that these differences are more subtle than those observed in glia, and may be further resolved by studies with larger sample numbers, as has been noted recently in studies of Alzheimer's Disease 11,16,17 .…”

Section: Discussionmentioning

confidence: 96%

Human disease-specific cell signatures in non-lesional tissue in Multiple Sclerosis detected by single-cell and spatial transcriptomics

Lam,

Lee,

Kosater

et al. 2023

Preprint

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Recent investigations of cell type changes in Multiple Sclerosis (MS) using single-cell profiling methods have focused on active lesional and peri-lesional brain tissue, and have implicated a number of peripheral and central nervous system cell types. However, an important question is the extent to which so-called “normal-appearing” non-lesional tissue in individuals with MS accumulate changes over the lifespan. Here, we compared post-mortem non-lesional brain tissue from donors with a pathological or clinical diagnosis of MS from the Religious Orders Study or Rush Memory and Aging Project (ROSMAP) cohorts to age– and sex-matched brains from persons without MS (controls). We profiled three brain regions using single-nucleus RNA-seq: dorsolateral prefrontal cortex (DLPFC), normal appearing white matter (NAWM) and the pulvinar in thalamus (PULV), from 15 control individuals, 8 individuals with MS, and 5 individuals with other detrimental pathologies accompanied by demyelination, resulting in a total of 78 samples. We identified region– and cell type-specific differences in non-lesional samples from individuals diagnosed with MS and/or exhibiting secondary demyelination with other neurological conditions, as compared to control donors. These differences included lower proportions of oligodendrocytes with expression of myelination related genes MOBP, MBP, PLP1, as well as higher proportions of CRYAB+ oligodendrocytes in all three brain regions. Among microglial signatures, we identified subgroups that were higher in both demyelination (TMEM163+/ERC2+), as well as those that were specifically higher in MS donors (HIF1A+/SPP1+) and specifically in donors with secondary demyelination (SOCS6+/MYO1E+), in both white and grey matter. To validate our findings, we generated Visium spatial transcriptomics data on matched tissue from 13 donors, and recapitulated our observations of gene expression differences in oligodendrocytes and microglia. Finally, we show that some of the differences observed between control and MS donors in NAWM mirror those previously reported between control WM and active lesions in MS donors. Overall, our investigation sheds additional light on cell type– and disease-specific differences present even in non-lesional white and grey matter tissue, highlighting widespread cellular signatures that may be associated with downstream pathological changes.

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“…Next, due to the known dysfunction and degeneration of neurons and synaptic dysfunction following head trauma and in neurodegenerative disease, we examined neurons, labeling subclusters using known layer-specific markers 12,[31][32][33][34][35][36] (Fig. 5a, Supplementary Fig.…”

Section: Synaptic Transcriptomic Changes and Loss Of Sulcal Excitator...mentioning

confidence: 99%

Repetitive head impacts induce neuronal loss and neuroinflammation in young athletes

Butler,

Pervaiz,

Ypsilantis

et al. 2024

Preprint

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Repetitive head impacts (RHI) sustained from contact sports are the largest risk factor for chronic traumatic encephalopathy (CTE). Currently, CTE can only be diagnosed after death and the multicellular cascade of events that trigger initial hyperphosphorylated tau (p-tau) deposition remain unclear. Further, the symptoms endorsed by young individuals with early disease are not fully explained by the extent of p-tau deposition, severely hampering development of therapeutic interventions. Here, we show that RHI exposure associates with a multicellular response in young individuals (<51 years old) prior to the onset of CTE p-tau pathology that correlates with number of years of RHI exposure. Leveraging single nucleus RNA sequencing of tissue from 8 control, 9 RHI-exposed, and 11 low stage CTE individuals, we identify SPP1+ inflammatory microglia, angiogenic and inflamed endothelial cell profiles, reactive astrocytes, and altered synaptic gene expression in excitatory and inhibitory neurons in all individuals with exposure to RHI. Surprisingly, we also observe a significant loss of cortical sulcus layer 2/3 neurons in contact sport athletes compared to controls independent of p-tau pathology. These results provide robust evidence that multiple years of RHI exposure is sufficient to induce lasting cellular alterations that may underlie p-tau deposition and help explain the early clinical symptoms observed in young former contact sport athletes. Furthermore, these data identify specific cellular responses to repetitive head impacts that may direct future identification of diagnostic and therapeutic strategies for CTE.

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Multicellular communities are perturbed in the aging human brain and Alzheimer’s disease

Cited by 43 publications

References 62 publications

Single-nucleus and spatial transcriptomic profiling of human temporal cortex and white matter reveals novel associations with AD pathology

Single-nucleus and spatial transcriptomic profiling of human temporal cortex and white matter reveals novel associations with AD pathology

Human disease-specific cell signatures in non-lesional tissue in Multiple Sclerosis detected by single-cell and spatial transcriptomics

Repetitive head impacts induce neuronal loss and neuroinflammation in young athletes

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