Single Cell Atlas of Human Putamen Reveals Disease Specific Changes in Synucleinopathies: Parkinson’s Disease and Multiple System Atrophy

Pande, Rahul; Huang, Yige; Teeple, Erin; Joshi, Piyush; Flores‐Morales, Amilcar; M, Latta Mahieu; Sp, Sardi; Cedazo-Mı́nguez, Ángel; Kw, Klinger; Sl, Madden; Rajpal, Deepak K.; Kumar, Dinesh

doi:10.1101/2021.05.06.442950

Cited by 5 publications

(4 citation statements)

References 42 publications

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“…Some inconsistency of expression patterns might be due to the absence of AD-specific microglia clusters in the human snRNA-Seq dataset, despite having a high resolution of 6,000 cells. This observation has been previously shown in other human snRNA-Seq datasets from brains affected by AD or other neurodegenerative diseases [66][67][68]. The difference between the human and animal models might be due to the fact that AD and other neurodegenerative diseases typically progress slowly, over many years, and all microglia populations may eventually end up transitioning to disease-associated states.…”

Section: Identification Of Stage-specific Eadam and Ladam Signatures ...supporting

confidence: 67%

Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes

Kim

Wei

et al. 2022

Mol Neurodegeneration

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Background Amongst risk alleles associated with late-onset Alzheimer’s disease (AD), those that converged on the regulation of microglia activity have emerged as central to disease progression. Yet, how canonical amyloid-β (Aβ) and tau pathologies regulate microglia subtypes during the progression of AD remains poorly understood. Methods We use single-cell RNA-sequencing to profile microglia subtypes from mice exhibiting both Aβ and tau pathologies across disease progression. We identify novel microglia subtypes that are induced in response to both Aβ and tau pathologies in a disease-stage-specific manner. To validate the observation in AD mouse models, we also generated a snRNA-Seq dataset from the human superior frontal gyrus (SFG) and entorhinal cortex (ERC) at different Braak stages. Results We show that during early-stage disease, interferon signaling induces a subtype of microglia termed Early-stage AD-Associated Microglia (EADAM) in response to both Aβ and tau pathologies. During late-stage disease, a second microglia subtype termed Late-stage AD-Associated Microglia (LADAM) is detected. While similar microglia subtypes are observed in other models of neurodegenerative disease, the magnitude and composition of gene signatures found in EADAM and LADAM are distinct, suggesting the necessity of both Aβ and tau pathologies to elicit their emergence. Importantly, the pattern of EADAM- and LADAM-associated gene expression is observed in microglia from AD brains, during the early (Braak II)- or late (Braak VI/V)- stage of the disease, respectively. Furthermore, we show that several Siglec genes are selectively expressed in either EADAM or LADAM. Siglecg is expressed in white-matter-associated LADAM, and expression of Siglec-10, the human orthologue of Siglecg, is progressively elevated in an AD-stage-dependent manner but not shown in non-AD tauopathy. Conclusions Using scRNA-Seq in mouse models bearing amyloid-β and/or tau pathologies, we identify novel microglia subtypes induced by the combination of Aβ and tau pathologies in a disease stage-specific manner. Our findings suggest that both Aβ and tau pathologies are required for the disease stage-specific induction of EADAM and LADAM. In addition, we revealed Siglecs as biomarkers of AD progression and potential therapeutic targets.

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Section: Identification Of Stage-specific Eadam and Ladam Signatures ...supporting

confidence: 67%

Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes

Kim

Wei

et al. 2022

Mol Neurodegeneration

View full text Add to dashboard Cite

show abstract

“…Some inconsistency of expression patterns might be due to the absence of ADspecific microglia clusters in the human snRNA-Seq dataset, despite having a high resolution of 6,000 cells. This observation has been previously shown in other human snRNA-Seq dataset in AD or other neurodegeneration [38][39][40] . The difference might be due to the fact that AD and other neurodegenerative disease typically progress slowly, over many years, and all microglia populations may end up transitioning to disease-associated states.…”

Section: Identification Of Stage-specific Eadam and Ladam Signatures In Alzheimer's Diseasesupporting

confidence: 83%

Amyloid-beta and tau pathologies are both necessary to induce novel stage-specific microglia subtypes during Alzheimer’s disease progression

Kim

Wei

et al. 2021

Preprint

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It is unknown whether specific microglia are selectively induced by amyloid-β(Aβ), tau pathologies, or both in combination. To address this, we use single-cell RNA-sequencing to profile mice bearing both Aβ and tau pathologies during Alzheimer's disease (AD). We identify novel microglia subtypes induced in a disease stage-specific manner. We show that during early-stage disease, interferon signaling induces a subtype of microglia termed EADAM. During late-stage disease, a second microglia subtype termed LADAM is detected. While EADAM and LADAM-like microglia are observed in other neurodegenerative models, the magnitude and composition of subtype markers are distinct from microglia observed with AD-like pathology. The pattern of EADAM- and LADAM-associated gene expression is observed in microglia from human AD, during the early and late stages of disease, respectively. Furthermore, we observe that several siglec genes are selectively expressed in either EADAM or LADAM. Siglecg is expressed in white-matter-associated LADAM, and expression of the human orthologue of Siglecg is progressively elevated in AD-stage-dependent manner but not shown in non-AD tauopathy. Our findings imply that both Aβ and tau pathologies are required for disease stage-specific induction of EADAM and LADAM.

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“…We analyzed single-nucleus RNA sequencing (snRNA-seq) of postmortem putamen brain tissue from three patients with PD and three healthy controls (Fig. 4a) 30,31 . The putamen is connected to the substantia nigra and is a pathologically relevant area in the midbrain that is susceptible to iron accumulation in PD 32 .…”

Section: Ferroptosis Signature Is Enriched In Neurodegenerative Diseasementioning

confidence: 99%

Microglia ferroptosis is regulated by SEC24B and contributes to neurodegeneration

et al. 2022

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Iron dysregulation has been implicated in multiple neurodegenerative diseases, including Parkinson’s disease (PD). Iron-loaded microglia are frequently found in affected brain regions, but how iron accumulation influences microglia physiology and contributes to neurodegeneration is poorly understood. Here we show that human induced pluripotent stem cell-derived microglia grown in a tri-culture system are highly responsive to iron and susceptible to ferroptosis, an iron-dependent form of cell death. Furthermore, iron overload causes a marked shift in the microglial transcriptional state that overlaps with a transcriptomic signature found in PD postmortem brain microglia. Our data also show that this microglial response contributes to neurodegeneration, as removal of microglia from the tri-culture system substantially delayed iron-induced neurotoxicity. To elucidate the mechanisms regulating iron response in microglia, we performed a genome-wide CRISPR screen and identified novel regulators of ferroptosis, including the vesicle trafficking gene SEC24B. These data suggest a critical role for microglia iron overload and ferroptosis in neurodegeneration.

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Single Cell Atlas of Human Putamen Reveals Disease Specific Changes in Synucleinopathies: Parkinson’s Disease and Multiple System Atrophy

Cited by 5 publications

References 42 publications

Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes

Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes

Amyloid-beta and tau pathologies are both necessary to induce novel stage-specific microglia subtypes during Alzheimer’s disease progression

Microglia ferroptosis is regulated by SEC24B and contributes to neurodegeneration

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