A Role of Low-Density Lipoprotein Receptor-Related Protein 4 (LRP4) in Astrocytic Aβ Clearance

Zhang, Hongsheng; Chen, Wenbing; Tan, Zhibing; Zhang, Lei; Dong, Zhaoqi; Cui, Wanpeng; Zhao, Kai; Wang, Hongsheng; Jing, Hongyang; Cao, Ruihua; Kim, Chae; Safar, Jiri; Xiong, Wen-Cheng; Mei, Lin

doi:10.1523/jneurosci.0250-20.2020

Cited by 44 publications

(44 citation statements)

References 113 publications

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“…Core members of the LDL receptor family have been related to APP tra cking and internalization and, therefore, they could determine the APP proteolytic processing and Aβ production, likely playing a role in AD pathogenesis [48][49][50][51]. For example, LRP1 increases APP endocytosis and generation of Aβ [52][53][54], while LRP1B retains APP at the cell surface [55].…”

Section: Discussionmentioning

confidence: 99%

LRP3, an apolipoprotein receptor that links reelin signalling and APP expression, is affected in Alzheimer's disease

Cuchillo-Ibáñez

Lennol

Escamilla

et al. 2021

Preprint

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Background. Members of the low-density lipoprotein (LDL) receptor family are involved in endocytosis and in transducing signals, but also in APP (amyloid precursor protein) processing and β-amyloid secretion. ApoER2/LRP8 is a member of this family with key roles in synaptic plasticity in the adult brain. ApoER2 is cleaved after the binding of its ligand, the reelin protein, generating an intracellular domain (ApoER2-ICD) that modulates reelin gene transcription itself. In this work, we have analysed whether ApoER2-ICD is able to regulate the expression of other members of the LDL receptor family. We focused on LRP3, the most unknown member of the LDL receptor family, whose precise physiological role and potential participation in pathological processes such as Alzheimer’s disease (AD) are still unknown.Methods. The effects of full-length ApoER2 and ApoER2-ICD overexpression on protein levels, in presence of recombinant reelin or Ab42 peptide, were evaluated by a microarray, qRT-PCRs and western blots. The expression of LRP3 was analysed in human frontal cortex extracts from AD and non-demented subjects by qRT-PCRs and western blot; and LRP3 interaction with other proteins was assessed by immunoprecipitation. In CHO cells overexpressing LRP3, protein levels of full-length APP and fragments were evaluated by western blots. Results. We have identified that ApoER2 overexpression increases LRP3 expression. Stimulation of ApoER2 signaling by reelin increased LRP3 levels, and the same occurred following ApoER2-ICD overexpression. In human frontal cortex extracts we demonstrate that LRP3 interacts with apolipoprotein E and APP. In extracts from AD subjects, the levels of LRP3 mRNA and protein were lower than those in control subjects. Interestingly, LRP3 transfection in CHO-PS70 cells induced a decrease of full-length APP levels and APP-CTF, and in the supernatant, levels of soluble APP fragments from the amyloidogenic (sAPPa) or non-amyloidogenic (sAPPβ) pathway, as well as Aβ peptides, were drastically reduced respect to mock-transfected cells.Limitations. There is a scarce knowledge of LRP3 physiological function as a neuronal receptor.Conclusion. We describe that LRP3 expression is regulated via ApoER2/reelin signaling, and its levels are affected in AD; similarly to other LDL receptors, LRP3 is involved in APP expression.

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Section: Discussionmentioning

confidence: 99%

LRP3, an apolipoprotein receptor that links reelin signalling and APP expression, is affected in Alzheimer's disease

Cuchillo-Ibáñez

Lennol

Escamilla

et al. 2021

Preprint

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“…Members of the LDLR family including LDLR and LRP1 are involved in astrocytic clearance of amyloid-β [ 104 , 113 ]. LRP4 also functions in amyloid-β clearance [ 33 ] and is expressed at higher levels in astrocytes than other members of the LDLR family. In this role, LRP4 promotes Aβ uptake by astrocytes likely by serving as a receptor for ApoE (as dot blot assays demonstrate that purified LRP4 ectodomain and human ApoE can physically interact), and therefore may play an important role in response to AD progression.…”

Section: From Development To Diseasementioning

confidence: 99%

“…In this role, LRP4 promotes Aβ uptake by astrocytes likely by serving as a receptor for ApoE (as dot blot assays demonstrate that purified LRP4 ectodomain and human ApoE can physically interact), and therefore may play an important role in response to AD progression. In mouse models of AD, loss of LRP4 in astrocytes exacerbated disease pathogenesis [ 33 ]. Furthermore, postmortem brain tissue from AD patients exhibited decreased levels of LRP4 [ 33 ].…”

Section: From Development To Diseasementioning

confidence: 99%

“…This indicates that these critical and diverse roles in neurodevelopment may be evolutionarily conserved. Further underscoring its importance in nervous system function and highlighting a potential link to human disease, the loss of LRP4 is linked to multiple neurodegenerative diseases including myasthenia gravis [ 28 , 29 , 30 ], amyotrophic lateral sclerosis (ALS) [ 31 ], and Alzheimer’s disease [ 32 , 33 ]. To begin to understand these roles, we will consider them in the context of three major categorizations, into which the functions for each of these roles can be placed: (1) whether LRP4 functions pre- or postsynaptically, (2) whether LRP4 functions in an Agrin-dependent or Agrin-independent manner, and (3) whether LRP4 functions in a cell-autonomous or non-cell autonomous fashion.…”

Section: Introductionmentioning

confidence: 99%

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Conservation and Innovation: Versatile Roles for LRP4 in Nervous System Development

DePew

Mosca

2021

JDB

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As the nervous system develops, connections between neurons must form to enable efficient communication. This complex process of synaptic development requires the coordination of a series of intricate mechanisms between partner neurons to ensure pre- and postsynaptic differentiation. Many of these mechanisms employ transsynaptic signaling via essential secreted factors and cell surface receptors to promote each step of synaptic development. One such cell surface receptor, LRP4, has emerged as a synaptic organizer, playing a critical role in conveying extracellular signals to initiate diverse intracellular events during development. To date, LRP4 is largely known for its role in development of the mammalian neuromuscular junction, where it functions as a receptor for the synaptogenic signal Agrin to regulate synapse development. Recently however, LRP4 has emerged as a synapse organizer in the brain, where new functions for the protein continue to arise, adding further complexity to its already versatile roles. Additional findings indicate that LRP4 plays a role in disorders of the nervous system, including myasthenia gravis, amyotrophic lateral sclerosis, and Alzheimer’s disease, demonstrating the need for further study to understand disease etiology. This review will highlight our current knowledge of how LRP4 functions in the nervous system, focusing on the diverse developmental roles and different modes this essential cell surface protein uses to ensure the formation of robust synaptic connections.

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“…ApoE, as one of LRP4 ligands, is essential for the development of the nervous system, the regulation of synaptic plasticity, neuroprotection, and the innervation of the muscle [8]. LRP4 interaction with ApoE promotes Aβ uptake [29].…”

Section: / 19mentioning

confidence: 99%

LRP4 LDLα Repeats of Astrocyte Enhances Dendrite Arborization of the Neuron

Yan¹,

Guo²,

Chen³

et al. 2020

Preprint

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Low-density lipoprotein receptor-related protein 4 (LRP4) is essential for inducing the neuromuscular junction formation in muscle fibers, and LRP4 plays a role of dendritic development and synaptogenesis in the central nervous system (CNS). As a member of the low-density lipoprotein receptor family, LRP4 contains an enormously large extracellular region possessing multiple LDLα repeats in the N-terminal. LRP4 only with extracellular domain acts as a similar mechanism of full-length LRP4 in muscles to stimulate acetylcholine receptor clustering. In this study, we elucidated that LDLα repeats of LRP4 maintained the body weight and survival rate. Dendritic branches of the neurons in Lrp4-null mice with LRP4 LDLα repeats residue were more than in Lrp4-null mice without residual LRP4 domain. Supplement with conditioned medium from LRP4 LDLα over expression cells, primary culture neurons achieved strong dendritic arborization ability. In addition, astrocytes with LRP4 LDLα repeats residue could promoted the dendrite arborization of neurons in primary co-cultured system. These observations signify that LRP4 LDLα repeats play an underlying prominent role in dendrite arborization.

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A Role of Low-Density Lipoprotein Receptor-Related Protein 4 (LRP4) in Astrocytic Aβ Clearance

Cited by 44 publications

References 113 publications

LRP3, an apolipoprotein receptor that links reelin signalling and APP expression, is affected in Alzheimer's disease

LRP3, an apolipoprotein receptor that links reelin signalling and APP expression, is affected in Alzheimer's disease

Conservation and Innovation: Versatile Roles for LRP4 in Nervous System Development

LRP4 LDLα Repeats of Astrocyte Enhances Dendrite Arborization of the Neuron

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