Dr. Jekyll and Mr. Hyde: ApoE explains opposing effects of neuronal LRP1

Strickland, Michael R.; Holtzman, David M.

doi:10.1172/jci127578

Cited by 10 publications

(11 citation statements)

References 16 publications

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“…Intriguingly, the present studies showed lipoprotein receptor levels were APOE genotype-dependent with the highest expression levels found in E4FAD mice and APOE4/4 individuals, most notably in the cerebrovasculature. Research conducted by Tachibana et al (2019) demonstrated that LRP1 participates more in the clearance of Aβ in the context of the APOE3 genotype whereas with the APOE4 genotype, LRP1 tends to contribute more to Aβ seeding [418], [419]. Given that the seeding of Aβ into oligomeric and insoluble species, which accumulate in extracellular Aβ plaques, has been shown to accelerate Aβ pathology [420], [421], the elevated levels of LRP1 exhibited by individuals with the APOE4 genotype reported in this Chapter may ultimately be detrimental and contribute to AD pathology.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E isoforms differentially regulate matrix metallopeptidase 9 function in Alzheimer’s disease

Ringland

Schweig

Paris

et al. 2020

Neurobiology of Aging

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Apolipoprotein E (APOE) is a major genetic risk factor for Alzheimer's disease (AD) and has been shown to influence amyloid-β (Aβ) clearance from the brain in an isoform-specific manner. Our prior work showed Aβ transit across the blood-brain-barrier was reduced by apoE4, compared to other apoE isoforms, due to elevated lipoprotein receptor shedding in brain endothelia. Recently, we demonstrated matrix metallopeptidase 9 (MMP-9) induces lipoprotein receptor proteolysis in an apoE isoform-dependent manner, which impacts Aβ elimination from the brain. The current studies interrogated the relationship between apoE and MMP-9 and found apoE dose-dependently reduced MMP-9 activity in a cell-free assay, with apoE4 showing a significantly weaker ability to inhibit MMP-9 function than apoE2 or apoE3. Moreover, these effects may be due to the reduced binding affinity of apoE4 for MMP-9 compared to apoE2 and apoE3 as revealed by kinetic binding studies. Elevated MMP-9 expression and activity was observed in the cerebrovasculature of both human and animal AD brain specimens with an APOE4 genotype. The apoE isoforms also lead to altered levels of MMP-9 secreted from brain endothelia cultures (apoE2

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Section: Discussionmentioning

confidence: 99%

Apolipoprotein E isoforms differentially regulate matrix metallopeptidase 9 function in Alzheimer’s disease

Ringland

Schweig

Paris

et al. 2020

Neurobiology of Aging

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“…Both BMP-2 or PPARγ agonists induce ApoE secretion in human PASMCs. Such PPARγ activation prevents PDGF-induced proliferation of PASMCs ( 61 ), as ApoE binds to LRP1 initiating the endocytosis and degradation of the LRP1/PDGFR-β/PDGF complex ( 67 , 110 ).…”

Section: Lrp8 Relays Apoe Signalmentioning

confidence: 99%

Interplay of Low-Density Lipoprotein Receptors, LRPs, and Lipoproteins in Pulmonary Hypertension

Calvier

Herz

Hansmann

2022

JACC: Basic to Translational Science

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“…ApoE KO mice were protected, whereas apoE4 mice had worsened pathology, suggesting that the apoE4 protein in these mice was exerting a toxic effect [43]. One hypothesis of how apoE4 promotes pathology in AD is through the initial seeding of Aβ [44]. An apoE-inducible expression mouse model bred with a mouse strain expressing the human amyloid precursor protein and presenilin with human mutations (APP/PS) was used to demonstrate that increasing expression of astrocytic human apoE4 enhanced amyloid deposition in mice when expression was turned on prior to initial seeding [45].…”

Section: Opposing Hypotheses On the Contribution Of Apoe4 To Admentioning

confidence: 99%

Targeting Apolipoprotein E for Alzheimer’s Disease: An Industry Perspective

Suidan

Ramaswamy

2019

IJMS

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Apolipoprotein E (apoE), a key lipid transport protein in the brain, is predominantly produced by astrocytes. Astrocytes are the most numerous cell type in the brain and are the main support network for neurons. They play a critical role in the synthesis and delivery of cholesterol in the brain. Humans have three common apoE isoforms, apoE2, apoE3 and apoE4, that show a strong genotype effect on the risk and age of onset for sporadic and late onset forms of Alzheimer’s disease (AD). Carriers of an ε4 allele have an increased risk of developing AD, while those with an ε2 allele are protected. Investigations into the contribution of apoE to the development of AD has yielded conflicting results and there is still much speculation about the role of this protein in disease. Here, we review the opposing hypotheses currently described in the literature and the approaches that have been considered for targeting apoE as a novel therapeutic strategy for AD. Additionally, we provide our perspective on the rationale for targeting apoE and the challenges that arise with respect to “drug-ability” of this target.

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Dr. Jekyll and Mr. Hyde: ApoE explains opposing effects of neuronal LRP1

Cited by 10 publications

References 16 publications

Apolipoprotein E isoforms differentially regulate matrix metallopeptidase 9 function in Alzheimer’s disease

Apolipoprotein E isoforms differentially regulate matrix metallopeptidase 9 function in Alzheimer’s disease

Interplay of Low-Density Lipoprotein Receptors, LRPs, and Lipoproteins in Pulmonary Hypertension

Targeting Apolipoprotein E for Alzheimer’s Disease: An Industry Perspective

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