ApoE facilitates the microglial response to amyloid plaque pathology

Ulrich, Jason D.; Ulland, Tyler K.; Mahan, Thomas E.; Nyström, Sofie; Nilsson, K. Peter R.; Song, Wilbur M.; Zhou, Yingyue; Reinartz, Mariska; Choi, Soo In; Jiang, Hong; Stewart, Floy R.; Anderson, Elise; Wang, Yaming; Colonna, Marco; Holtzman, David M.

doi:10.1084/jem.20171265

Cited by 213 publications

(206 citation statements)

References 57 publications

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“…Previous studies from our lab and others showed that complete ablation [59][60][61][62][63] or reduction [8][9][10] of apoE levels results in a decrease of Aβ pathology, particularly a marked reduction of fibrillar Aβ in the brain. However, it was difficult to assess the contribution of peripheral apoE ablation to phenotypes found in the brain in complete Fig.…”

Section: Plasma Lipid Alterations In Mice Lacking Liver-derived Apoementioning

confidence: 66%

Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model

Huynh

Wang

Tran

et al. 2019

Mol Neurodegeneration

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Background The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease (AD). ApoE is produced by both astrocytes and microglia in the brain, whereas hepatocytes produce the majority of apoE found in the periphery. Studies using APOE knock-in and transgenic mice have demonstrated a strong isoform-dependent effect of apoE on the accumulation of amyloid-β (Aβ) deposition in the brain in the form of both Aβ-containing amyloid plaques and cerebral amyloid angiopathy. However, the specific contributions of different apoE pools to AD pathogenesis remain unknown. Methods We have begun to address these questions by generating new lines of APOE knock-in (APOE-KI) mice (ε2/ε2, ε3/ε3, and ε4/ε4) where the exons in the coding region of APOE are flanked by loxP sites, allowing for cell type-specific manipulation of gene expression. We assessed these mice both alone and after crossing them with mice with amyloid deposition in the brain. Using biochemical and histological methods. We also investigated how removal of APOE expression from hepatocytes affected cerebral amyloid deposition. Results As in other APOE knock-in mice, apoE protein was present predominantly in astrocytes in the brain under basal conditions and was also detected in reactive microglia surrounding amyloid plaques. Primary cultured astrocytes and microglia from the APOE-KI mice secreted apoE in lipoprotein particles of distinct size distribution upon native gel analysis with microglial particles being substantially smaller than the HDL-like particles secreted by astrocytes. Crossing of APP/PS1 transgenic mice to the different APOE-KI mice recapitulated the previously described isoform-specific effect (ε4 > ε3) on amyloid plaque and Aβ accumulation. Deletion of APOE in hepatocytes did not alter brain apoE levels but did lead to a marked decrease in plasma apoE levels and changes in plasma lipid profile. Despite these changes in peripheral apoE and on plasma lipids, cerebral accumulation of amyloid plaques in APP/PS1 mice was not affected. Conclusions Altogether, these new knock-in strains offer a novel and dynamic tool to study the role of APOE in AD pathogenesis in a spatially and temporally controlled manner.

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Section: Plasma Lipid Alterations In Mice Lacking Liver-derived Apoementioning

confidence: 66%

Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model

Huynh

Wang

Tran

et al. 2019

Mol Neurodegeneration

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“…Apoe −/− mice were significantly associated with ivory module (N = 64, p = 9.7 × 10 −6 ), while the skyblue3 (N = 80, p = 4.6 × 10 −13 ) (Figure 3; Figure 4; Supplemental Table 3) module were significantly associated with both Apoe −/− and APOEε4 strains. Pathway analysis identified that the ivory mouse module was enriched in inflammation and microglia related pathways such as osteoclast differentiation, staphylococcus aures infection, phagosome, and endocytosis (Figure 2B), implicating an important role of Apoe in inflammatory and microglia related functions [40–42]. Brown (N = 1778, p = 3.1 × 10 −7 ), lightcyan1 (N = 1206, p = 1.9 × 10 −5 ), black (N = 685, p = 2.0 × 10 −2 ), plum1 (N = 80, p = 1.0 × 10 −2 ), and brown4 (N = 55, p = 0.04) modules were significantly associated with Clu −/− (Figure 3; Figure 4; Supplemental Table 3).…”

Section: Resultsmentioning

confidence: 99%

Genetic perturbations of disease risk genes in mice capture transcriptomic signatures of late-onset Alzheimer’s disease

Pandey

Graham

Uyar

et al. 2019

Preprint

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BackgroundNew genetic and genomic resources have identified multiple genetic risk factors for late-onset Alzheimer’s disease (LOAD) and characterized this common dementia at the molecular level. Experimental studies in model organisms can validate these associations and elucidate the links between specific genetic factors and transcriptomic signatures. Animal models based on LOAD-associated genes can potentially connect common genetic variation with LOAD transcriptomes, thereby providing novel insights into basic biological mechanisms underlying the disease.MethodsWe performed RNA-Seq on whole brain samples from a panel of six-month-old female mice, each carrying one of the following mutations: homozygous deletions of Apoe and Clu; hemizygous deletions of Bin1 and Cd2ap; and a transgenic APOEε4. Similar data from a transgenic APP/PS1 model was included for comparison to early-onset variant effects. Weighted gene co-expression network analysis (WGCNA) was used to identify modules of correlated genes and each module was tested for differential expression by strain. We then compared mouse modules with human postmortem brain modules from the Accelerating Medicine’s Partnership for AD (AMP-AD) to determine the LOAD-related processes affected by each genetic risk factor.ResultsMouse modules were significantly enriched in multiple AD-related processes, including immune response, inflammation, lipid processing, endocytosis, and synaptic cell function. WGCNA modules were significantly associated with Apoe−/−, APOEε4, Clu−/−, and APP/PS1 mouse models. Apoe−/−, GFAP-driven APOEε4, and APP/PS1 driven modules overlapped with AMP-AD inflammation and microglial modules; Clu−/− driven modules overlapped with synaptic modules; and APP/PS1 modules separately overlapped with lipid-processing and metabolism modules.ConclusionsThis study of genetic mouse models provides a basis to dissect the role of AD risk genes in relevant AD pathologies. We determined that different genetic perturbations affect different molecular mechanisms comprising AD, and mapped specific effects to each risk gene. Our approach provides a platform for further exploration into the causes and progression of AD by assessing animal models at different ages and/or with different combinations of LOAD risk variants.

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“…Thus, a potential cycle involves initial microglial reaction, which results in upregulation and secretion of ApoE, leading to altered amyloid deposition with ApoE incorporated into the plaque, which binds to TREM2 and continues the cycle. This potential cycle is supported by work demonstrating that APP/PS1 mice crossed to Apoe-KO mice have significant reductions in the number of plaque-associated microglia (Ulrich et al, 2018). Furthermore, treatment of an AD mouse model with antibody specifically against non-lipidated ApoE (including that found in plaques) reduced amyloid deposition (Liao et al, 2018).…”

Section: Trem2 Signaling Networkmentioning

confidence: 94%

Immune Signaling in Neurodegeneration

2019

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Neurodegenerative diseases of the central nervous system progressively rob patients of their memory, motor function, and ability to perform daily tasks. Advances in genetics and animal models are beginning to unearth an unexpected role of the immune system in disease onset and pathogenesis; however, the role of cytokines, growth factors, and other immune signaling pathways in disease pathogenesis is still being examined. Here we review recent genetic risk and genome-wide association studies and emerging mechanisms for three key immune pathways implicated in disease, the growth factor TGF-b, the complement cascade, and the extracellular receptor TREM2. These immune signaling pathways are important under both healthy and neurodegenerative conditions, and recent work has highlighted new functional aspects of their signaling. Finally, we assess future directions for immune-related research in neurodegeneration and potential avenues for immune-related therapies.

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ApoE facilitates the microglial response to amyloid plaque pathology

Abstract: Increasing evidence suggests that apoE influences the innate immune response in neurodegeneration. Here, Ulrich et al. report that apoE influences amyloid plaque morphology and the microglial response to amyloid plaques, along with plaque-associated neuronal toxicity.

Cited by 213 publications

References 57 publications

Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model

Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model

Genetic perturbations of disease risk genes in mice capture transcriptomic signatures of late-onset Alzheimer’s disease

Immune Signaling in Neurodegeneration

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