Human microglial state dynamics in Alzheimer’s disease progression

Sun, Na; Victor, Matheus B.; Park, Yongjin P.; Xiong, Xushen; Scannail, Aine Ni; Leary, Noelle; Prosper, Shaniah; Viswanathan, Soujanya; Luna, Xochitl; Boix, Carles A.; James, Benjamin T.; Tanigawa, Yosuke; Galani, Kyriaki; Mathys, Hansruedi; Jiang, Xueqiao; Ng, Ayesha P.; Bennett, David A.; Tsai, Li-Huei; Kellis, Manolis

doi:10.1016/j.cell.2023.08.037

Cited by 126 publications

(57 citation statements)

References 95 publications

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“… In contrast, TSEL-treated AD mice gene ontology (GO) revealed that the DEGs are significantly enriched in biological processes that include microglia differentiation, activation migration, and negative regulation of immune cell activation (Figure K) . Moreover, RNAseq revealed that TREM2 encourages the conversion of microglia to the DAM phenotype, which is responsible for Aβ phagocytosis. , To sum up, TSEL treatment significantly inhibited neuroinflammation, demonstrating the synergistic effect of TREM2 and BACE1 that activated M2 microglia and decreased M1 activation, leading to a decrease in Aβ deposition and improved cognition in AD mice.…”

Section: Resultsmentioning

confidence: 94%

“…48 Moreover, RNAseq revealed that TREM2 encourages the conversion of microglia to the DAM phenotype, which is responsible for Aβ phagocytosis. 49,50 To sum up, TSEL treatment significantly inhibited neuroinflammation, demonstrating the synergistic effect of TREM2 and BACE1 that activated M2 microglia and decreased M1 activation, leading to a decrease in Aβ deposition and improved cognition in AD mice.…”

Section: Resultsmentioning

confidence: 97%

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Biomimetic Nanovesicles as a Dual Gene Delivery System for the Synergistic Gene Therapy of Alzheimer’s Disease

Jiang,

Cai,

Yang

et al. 2024

ACS Nano

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The association between dysfunctional microglia and amyloid-β (Aβ) is a fundamental pathological event and increases the speed of Alzheimer's disease (AD). Additionally, the pathogenesis of AD is intricate and a single drug may not be enough to achieve a satisfactory therapeutic outcome. Herein, we reported a facile and effective gene therapy strategy for the modulation of microglia function and intervention of Aβ anabolism by ROS-responsive biomimetic exosome-liposome hybrid nanovesicles (designated as TSEL). The biomimetic nanovesicles codelivery βsite amyloid precursor protein cleaving enzyme-1 (BACE1) siRNA (siBACE1) and TREM2 plasmid (pTREM2) gene drug efficiently penetrate the blood−brain barrier and enhance the drug accumulation at AD lesions with the help of exosomes homing ability and angiopep-2 peptides. Specifically, an upregulation of TREM2 expression can reprogram microglia from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype while also restoring its capacity to phagocytose Aβ and its nerve repair function. In addition, siRNA reduces the production of Aβ plaques at the source by knocking out the BACE1 gene, which is expected to further enhance the therapeutic effect of AD. The in vivo study suggests that TSEL through the synergistic effect of two gene drugs can ameliorate APP/PS1 mice cognitive impairment by regulating the activated microglial phenotype, reducing the accumulation of Aβ, and preventing the retriggering of neuroinflammation. This strategy employs biomimetic nanovesicles for the delivery of dual nucleic acids, achieving synergistic gene therapy for AD, thus offering more options for the treatment of AD.

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Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 97%

Biomimetic Nanovesicles as a Dual Gene Delivery System for the Synergistic Gene Therapy of Alzheimer’s Disease

Jiang,

Cai,

Yang

et al. 2024

ACS Nano

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“…Single-cell sequencing studies of human AD brains have consistently reported microglial subsets characterized by cellular stress and altered metabolism. [34][35][36] To probe these datasets for ATF4 network enrichment, we used the upstream regulator analysis tool of Ingenuity Pathway Analysis 37 . We found that many disease-associated human microglia subsets from two recent studies 35,36 showed a selective enrichment of the ATF4 target gene network (Fig.…”

Section: Isr Is Activated In Dark Microgliamentioning

confidence: 99%

“…[34][35][36] To probe these datasets for ATF4 network enrichment, we used the upstream regulator analysis tool of Ingenuity Pathway Analysis 37 . We found that many disease-associated human microglia subsets from two recent studies 35,36 showed a selective enrichment of the ATF4 target gene network (Fig. 1c, Supplementary Fig.…”

Section: Isr Is Activated In Dark Microgliamentioning

confidence: 99%

Integrated stress response associated with dark microglia promotes microglial lipogenesis and contributes to neurodegeneration

Flury,

Aljayousi,

Aziz

et al. 2024

Preprint

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Microglia, the brain′s primary resident immune cells, are a heterogeneous population and can assume phenotypes with diverse functional outcomes on brain homeostasis. In Alzheimer′s disease (AD), where microglia are a leading causal cell type, microglia subsets with protective functions have been well characterized. Yet, the identity of microglia subsets that drive neurodegeneration remains unresolved. Here, we identify a neurodegenerative microglia phenotype that is characterized by a conserved stress signaling pathway, the integrated stress response (ISR). Using mouse models to activate or inhibit ISR in microglia, we show that ISR underlies the ultrastructurally distinct ″dark″ microglia subset linked to pathological synapse loss. Inducing microglial ISR in murine AD models exacerbates neurodegenerative pathologies, such as Tau pathology and synapse loss. Conversely, inhibiting microglial ISR in AD models ameliorates these pathologies. Mechanistically, we present evidence that ISR promotes the secretion of toxic long-chain lipids that impair neuron and oligodendrocyte homeostasis in vitro. Accordingly, small molecule-based inhibition of lipid synthesis in AD models ameliorates synapse loss. Our results demonstrate that activation of ISR within microglia represents a novel pathway contributing to neurodegeneration and suggest that this may be sustained, at least in part, by the secretion of long-chain lipids from ISR-activated microglia.

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“…Brain myeloid-origin immune cells, including microglia and perivascular macrophages (PVMs), play crucial roles in the pathogenesis of AD [1][2][3][4][7][8][9][10] , providing neuroprotective benefits by clearing lesions, but also exacerbating the disease through the induction of excessive neuroinflammation 11 . While previous studies utilizing single-nucleus/-cell RNA sequencing (snRNA-seq/scRNA-seq) have made significant progress describing complex functional roles of murine and human microglia in AD 4,[12][13][14][15] , challenges with characterizing the wide spectrum of microglial heterogeneity and identifying more nuanced AD-associated subtypes still remain, largely due to limited sample sizes and differences in the single-cell technologies used. Among the issues that arise is the failure of nuclear fractions in snRNA-seq from frozen tissue to capture key genes related to microglial adaptation and response to pathogenic lesions 16 .…”

Section: Mainmentioning

confidence: 99%

Plasticity of Human Microglia and Brain Perivascular Macrophages in Aging and Alzheimer’s Disease

Lee,

Vicari,

Porras

et al. 2023

Preprint

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Microglia and perivascular macrophages, myeloid-origin resident immune cells in the human brain, play crucial roles in Alzheimer's disease (AD)1-4. However, the field lacks a unified taxonomy describing their heterogeneity and plasticity5. To address this, we applied single-cell profiling to two independent, demographically diverse cohorts. The first comprises 543,012 viable myeloid cells from 137 unique postmortem brain specimens, while the second consists of 289,493 myeloid nuclei from 1,470 donors. Collectively, they cover the human lifespan and varying degrees of AD neuropathology. We identify 13 transcriptionally distinct myeloid subtypes, including the "GPNMB" subtype that proliferates with AD. We distinguish two contrasting homeostatic microglial states in AD and with aging: the first ("FRMD4A") wanes over time, while the second ("PICALM") becomes more prevalent. By prioritizing AD-risk genes, including PTPRG, DPYD, and IL15, and placing them into a regulatory hierarchy, we identify common upstream transcriptional regulators, namely MITF and KLF12, that regulate the expression of AD-risk genes in the opposite directions. Through the construction of cell-to-cell interaction networks, we identify candidate ligand-receptor pairs, including APOE:SORL1 and APOE:TREM2, associated with AD progression. We show polygenic risk for AD predisposes and prioritize the GPNMB subtype as a therapeutic target of early intervention. Our findings delineate the relationship between distinct functional states of myeloid cells and their pathophysiological response to aging and AD, providing a significant step toward the mechanistic understanding of the roles of microglia in AD and the identification of novel therapeutics.

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Human microglial state dynamics in Alzheimer’s disease progression

Cited by 126 publications

References 95 publications

Biomimetic Nanovesicles as a Dual Gene Delivery System for the Synergistic Gene Therapy of Alzheimer’s Disease

Biomimetic Nanovesicles as a Dual Gene Delivery System for the Synergistic Gene Therapy of Alzheimer’s Disease

Integrated stress response associated with dark microglia promotes microglial lipogenesis and contributes to neurodegeneration

Plasticity of Human Microglia and Brain Perivascular Macrophages in Aging and Alzheimer’s Disease

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