<i>APOE</i> modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge

Lee, Sangderk; Devanney, Nicholas; Golden, Lesley R.; Smith, Cathryn T.; Schwarz, James L.; Walsh, Adeline E.; Clarke, Harrison A.; Goulding, Danielle S.; Allenger, Elizabeth J.; Morillo-Segovia, Gabriella; Friday, Cassi M.; Gorman, Amy A.; Hawkinson, Tara R.; MacLean, Steven M.; Williams, Holden C.; Sun, Ramon C.; Morganti, Josh M.; Johnson, Lance A.

doi:10.1101/2022.05.17.492361

Cited by 4 publications

(5 citation statements)

References 111 publications

(146 reference statements)

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“…8C ). Furthermore, using recently published subtype-specific vascular marker genes (Vanlandewijck et al ., 2018; Barisano et al ., 2022; Lee et al ., 2022), distinct cell clusters were identified, including smooth muscle cells (SMC), vascular leptomeningeal cells, pericytes, endothelial cells, and astrocytes ( Fig. 8D-E ).…”

Section: Resultsmentioning

confidence: 99%

Loss of TREM2 exacerbates parenchymal amyloid pathology but diminishes CAA in Tg-SwDI mice

Zhong,

Xu,

Williams

et al. 2023

Preprint

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease, and it is the most common cause of dementia worldwide. Recent genome-wide association studies (GWAS) identified TREM2 (triggering receptor expressed on myeloid cells 2) as one of the major risk factors for AD. TREM2 is a surface receptor expressed on microglia and largely mediates microglial functions and immune homeostasis in the brain. The functions of TREM2 in AD pathogenesis, including in the formation of the key pathology parenchymal amyloid-β (Aβ) plaques, have been investigated by introducingTrem2deficiency in AD mouse models. However, the role of TREM2 in cerebrovascular amyloidosis, in particular cerebral amyloid angiopathy (CAA) remains unexplored. CAA features Aβ deposition along the cerebral vessels, signifying an intersection between AD and vascular dysfunction. Using a well-characterized CAA-prone, transgenic mouse model of AD, Tg-SwDI (SwDI), we found that loss of TREM2 led to a marked increase in overall Aβ load in the brain, but a dramatic decrease in CAA in microvessel-rich regions, along with reduced microglial association with CAA. Transcriptomic analysis revealed that in the absence ofTrem2, microglia were activated but trapped in transition to the fully reactive state. Like microglia, perivascular macrophages were activated with upregulation of cell junction related pathways inTrem2-deficient SwDI mice. In addition, vascular mural cells and astrocytes exhibited distinct responses toTrem2deficiency, contributing to the pathological changes in the brain ofTrem2-null SwDI mice. Our study provides the first evidence that TREM2 differentially modulates parenchymal and vascular Aβ pathologies, which may have significant implications for both TREM2- and Aβ-targeting therapies for AD.

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Section: Resultsmentioning

confidence: 99%

Loss of TREM2 exacerbates parenchymal amyloid pathology but diminishes CAA in Tg-SwDI mice

Zhong,

Xu,

Williams

et al. 2023

Preprint

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“…Several recent investigations in animal models of AD support our findings. For example, the APOE genotype modulates microglial response in AD, with APOEε4 being associated with multiple microglial-related detrimental downstream effects (e.g., protein aggregation, neurodegeneration, and dysfunctional immunometabolic response) (25,(27)(28)(29)(30). Further experiments showed that the APOEε4 genotype associates with changes in the transcriptional profile of microglia from a homeostatic state to a disease-associated state across AD progression (31,32) and that the activation of microglial-related proteins [e.g., triggering receptor expressed on myeloid cells 2 (TREM2); (33)(34)(35)(36)] is directly associated with ApoE signaling (37).…”

Section: Discussionmentioning

confidence: 99%

“…However, recent animal studies suggest that the APOEε4 genotype may also contribute to AD pathogenesis through Aβ-independent pathways by potentiating brain inflammation, tau accumulation, and neurodegeneration (25,26). Although robust experimental evidence indicates that the APOE genotype modulates microglial response in AD (25,(27)(28)(29)(30), it remains to be elucidated whether the presence of the APOEε4 allele is associated with microglial activation in the AD human brain. The characterization of this association in living individuals is critical to confirm the Aβ-independent detrimental effects of APOEε4 on microglia homeostasis and to support the development of therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

APOE ε4 associates with microglial activation independently of Aβ plaques and tau tangles

et al. 2023

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Animal studies suggest that the apolipoprotein E ε4 ( APOE ε4) allele is a culprit of early microglial activation in Alzheimer’s disease (AD). Here, we tested the association between APOE ε4 status and microglial activation in living individuals across the aging and AD spectrum. We studied 118 individuals with positron emission tomography for amyloid-β (Aβ; [ 18 F]AZD4694), tau ([ 18 F]MK6240), and microglial activation ([ 11 C]PBR28). We found that APOE ε4 carriers presented increased microglial activation relative to noncarriers in early Braak stage regions within the medial temporal cortex accounting for Aβ and tau deposition. Furthermore, microglial activation mediated the Aβ-independent effects of APOE ε4 on tau accumulation, which was further associated with neurodegeneration and clinical impairment. The physiological distribution of APOE mRNA expression predicted the patterns of APOE ε4-related microglial activation in our population, suggesting that APOE gene expression may regulate the local vulnerability to neuroinflammation. Our results support that the APOE ε4 genotype exerts Aβ-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition.

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“…For example, the APOE genotype modulates microglial response in AD, with APOE ε4 being associated with multiple microglial-related detrimental downstream effects ( e . g ., protein aggregation, neurodegeneration, and dysfunctional immunometabolic response) (25, 27-30) . Further experiments showed that the APOE ε4 genotype associates with changes in the transcriptional profile of microglia from a homeostatic state to a disease-associated state across AD progression (31, 32) and that the activation of microglial-related proteins ( e .…”

Section: Discussionmentioning

confidence: 99%

“…However, recent animal studies suggest that the APOE ε4 genotype may also contribute to AD pathogenesis through Aβ-independent pathways by potentiating brain inflammation, tau accumulation, and neurodegeneration (25, 26) . Although robust experimental evidence indicates that the APOE genotype modulates microglial response in AD (25, 27-30) , it remains to be elucidated whether APOE ε4 carriership is associated with microglial activation in the AD human brain. The characterization of this association in living individuals is critical to confirm the Aβ-independent detrimental effects of APOE ε4 on microglia homeostasis and to support the development of novel therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

APOEε4 carriership associates with microglial activation independently of Aβ plaques and tau tangles

Ferrari‐Souza

Lussier

Leffa

et al. 2022

Preprint

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Microglial activation is an early phenomenon in Alzheimer′s disease (AD) that may occur prior to and independently of amyloid-β (Aβ) aggregation. Recent studies in transgenic animal models suggest that the apolipoprotein E ϵ4 (APOEϵ4) allele may be a culprit of early microglial activation in AD. However, it is unclear whether the APOEϵ4 genotype is associated with microglial reactivity in the living human brain. Here, we tested whether APOEϵ4 carriership is associated with microglial activation in individuals across the aging and AD spectrum. We studied 118 individuals who had positron emission tomography (PET) for Aβ ([18F]AZD4694), tau ([18F]MK6240), and microglial activation ([11C]PBR28), as well as clinical, genetic, and magnetic resonance imaging data. We found that APOEϵ4 carriership was associated with increased microglial activation mainly in early Braak-staging regions within the medial temporal cortex, and this effect of APOEϵ4 was independent of Aβ and tau deposition. Furthermore, microglial activation mediated the Aβ-independent effects of APOEϵ4 on downstream tau accumulation, neurodegeneration, and clinical impairment. Interestingly, the physiological distribution of APOE mRNA expression, obtained from the Allen Human Atlas, predicted the patterns of APOEϵ4-related microglial activation in our population, suggesting that the deleterious effects of APOEϵ4 occur at the level of gene expression. These results support a model in which the APOEϵ4 has Aβ-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition. Our findings provide a rationale for the development of novel AD therapies targeting the interplay between ApoE and neuroinflammation.

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APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge

Cited by 4 publications

References 111 publications

Loss of TREM2 exacerbates parenchymal amyloid pathology but diminishes CAA in Tg-SwDI mice

Loss of TREM2 exacerbates parenchymal amyloid pathology but diminishes CAA in Tg-SwDI mice

APOE ε4 associates with microglial activation independently of Aβ plaques and tau tangles

APOEε4 carriership associates with microglial activation independently of Aβ plaques and tau tangles

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