LRP1 in vascular mural cells modulates cerebrovascular integrity and function in the presence of APOE4

Oue, Hiroshi; Yu, Yun William; Qiao, Wenhui; Chen, Yuanxin; Ren, Yingxue; Kurti, Aishe; Shue, Francis; Parsons, Tammee M.; Perkerson, Ralph B.; Kawatani, Keiji; Wang, Ni; Starling, Skylar C; Roy, Bhaskar; Mosneag, Ioana-Emilia; Aikawa, Tomonori; Holm, Marie-Louise; Liu, Chia-Chen; Inoue, Yasuteru; Sullivan, Patrick M.; Asmann, Yan W.; Kim, Betty Ys; Bu, Guojun; Kanekiyo, Takahisa

doi:10.1172/jci.insight.163822

Cited by 10 publications

(4 citation statements)

References 65 publications

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“…Therefore, we sought to determine whether APOE affected microglial reactivity through interaction with LRP1 in NMOSD mice. Expression of LRP1 (28) was abundant in brain microglial cells, but both the percentage of LRP1 + microglia (P = 0.030; left, Fig. 6A) and the LRP1 + microglial cell counts (P = 0.019; right, Fig.…”

Section: Genetic Knockdown Of Lrp1 Inhibited the Effect Of Apoe On Nm...mentioning

confidence: 97%

“…The low-density lipoprotein receptor-related protein 1 (LRP1) is a major receptor for APOE in the brain (28,29), and microglial LRP1 is protective during CNS autoimmunity (30). Therefore, we sought to determine whether APOE affected microglial reactivity through interaction with LRP1 in NMOSD mice.…”

Section: Genetic Knockdown Of Lrp1 Inhibited the Effect Of Apoe On Nm...mentioning

confidence: 99%

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APOE from patient-derived astrocytic extracellular vesicles alleviates neuromyelitis optica spectrum disorder in a mouse model

Jiang,

Li,

et al. 2024

Sci. Transl. Med.

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Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy of the central nervous system, mediated by antibodies against aquaporin-4 water channel protein (AQP4-Abs), resulting in damage of astrocytes with subsequent demyelination and axonal damage. Extracellular communication through astrocyte-derived extracellular vesicles (ADEVs) has received growing interest in association with astrocytopathies. However, to what extent ADEVs contribute to NMOSD pathogenesis remains unclear. Here, through proteomic screening of patient-derived ADEVs, we observed an increase in apolipoprotein E (APOE)–rich ADEVs in patients with AQP4-Abs–positive NMOSD. Intracerebral injection of the APOE-mimetic peptide APOE 130–149 attenuated microglial reactivity, neuroinflammation, and brain lesions in a mouse model of NMOSD. The protective effect of APOE in NMOSD pathogenesis was further established by the exacerbated lesion volume in APOE-deficient mice, which could be rescued by exogenous APOE administration. Genetic knockdown of the APOE receptor lipoprotein receptor–related protein 1 (LRP1) could block the restorative effects of APOE 130–149 administration. The transfusion ADEVs derived from patients with NMOSD and healthy controls also alleviated astrocyte loss, reactive microgliosis, and demyelination in NMOSD mice. The slightly larger beneficial effect of patient-derived ADEVs as compared to ADEVs from healthy controls was further augmented in APOE −/− mice. These results indicate that APOE from astrocyte-derived extracellular vesicles could mediate disease-modifying astrocyte-microglia cross-talk in NMOSD.

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Section: Genetic Knockdown Of Lrp1 Inhibited the Effect Of Apoe On Nm...mentioning

confidence: 97%

Section: Genetic Knockdown Of Lrp1 Inhibited the Effect Of Apoe On Nm...mentioning

confidence: 99%

APOE from patient-derived astrocytic extracellular vesicles alleviates neuromyelitis optica spectrum disorder in a mouse model

Jiang,

Li,

et al. 2024

Sci. Transl. Med.

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“…In the CNS, LRP1 is expressed by neuronal and glia cell populations ( Auderset et al, 2016a ). Furthermore, the LRP1 receptor is prominent in the blood-brain-barrier (BBB) where it is present in endothelia, astrocytic end-feet, pericytes and smooth muscle cells ( Ma et al, 2018 ; Storck et al, 2021b ; Oue et al, 2023 ). Interestingly, LRP1 is also expressed in the neural stem cell compartment, by NSPCs ( Hennen et al, 2013 ; Auderset et al, 2016b ).…”

Section: Introductionmentioning

confidence: 99%

“…The functions of LRP1 were assessed against an APOE3 or APOE4 background. In the latter, the removal of LRP1 led to impaired spatial memory, accompanied by a disruption of the BBB ( Oue et al, 2023 ). These studies clearly emphasize that LRP1 plays important roles in the BBB and partakes in the clearance of Abeta ( Cai et al, 2018 ; Eggert et al, 2018 ; Storck et al, 2021a ; Petrushanko et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Low-density lipoprotein receptor-related protein-1 (LRP1) in the glial lineage modulates neuronal excitability

Faissner

2023

Front. Netw. Physiol.

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The low-density lipoprotein related protein receptor 1 (LRP1), also known as CD91 or α-Macroglobulin-receptor, is a transmembrane receptor that interacts with more than 40 known ligands. It plays an important biological role as receptor of morphogens, extracellular matrix molecules, cytokines, proteases, protease inhibitors and pathogens. In the CNS, it has primarily been studied as a receptor and clearance agent of pathogenic factors such as Aβ-peptide and, lately, Tau protein that is relevant for tissue homeostasis and protection against neurodegenerative processes. Recently, it was found that LRP1 expresses the Lewis-X (Lex) carbohydrate motif and is expressed in the neural stem cell compartment. The removal of Lrp1 from the cortical radial glia compartment generates a strong phenotype with severe motor deficits, seizures and a reduced life span. The present review discusses approaches that have been taken to address the neurodevelopmental significance of LRP1 by creating novel, lineage-specific constitutive or conditional knockout mouse lines. Deficits in the stem cell compartment may be at the root of severe CNS pathologies.

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Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference

Kloske,

Belloy,

Blue

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONThe apolipoprotein E gene (APOE) is an established central player in the pathogenesis of Alzheimer's disease (AD), with distinct apoE isoforms exerting diverse effects. apoE influences not only amyloid‐beta and tau pathologies but also lipid and energy metabolism, neuroinflammation, cerebral vascular health, and sex‐dependent disease manifestations. Furthermore, ancestral background may significantly impact the link between APOE and AD, underscoring the need for more inclusive research.METHODSIn 2023, the Alzheimer's Association convened multidisciplinary researchers at the “AAIC Advancements: APOE” conference to discuss various topics, including apoE isoforms and their roles in AD pathogenesis, progress in apoE‐targeted therapeutic strategies, updates on disease models and interventions that modulate apoE expression and function.RESULTSThis manuscript presents highlights from the conference and provides an overview of opportunities for further research in the field.DISCUSSIONUnderstanding apoE's multifaceted roles in AD pathogenesis will help develop targeted interventions for AD and advance the field of AD precision medicine.Highlights APOE is a central player in the pathogenesis of Alzheimer's disease. APOE exerts a numerous effects throughout the brain on amyloid‐beta, tau, and other pathways. The AAIC Advancements: APOE conference encouraged discussions and collaborations on understanding the role of APOE.

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LRP1 in vascular mural cells modulates cerebrovascular integrity and function in the presence of APOE4

Cited by 10 publications

References 65 publications

APOE from patient-derived astrocytic extracellular vesicles alleviates neuromyelitis optica spectrum disorder in a mouse model

APOE from patient-derived astrocytic extracellular vesicles alleviates neuromyelitis optica spectrum disorder in a mouse model

Low-density lipoprotein receptor-related protein-1 (LRP1) in the glial lineage modulates neuronal excitability

Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference

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