LRP8 (ApoER2) Protein

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LRP8 (ApoER2) Protein

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LRP8 (ApoER2) Protein

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">LRP8 (ApoER2)</th>
</tr>
<tr>
<td class="label">Gene</td>
<td>[LRP8](/genes/lrp8)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9Y6X0" target="_blank">Q9Y6X0</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td><a href="https://www.rcsb.org/structure/1JYH" target="_blank">1JYH</a>, <a href="https://www.rcsb.org/structure/1OXM" target="_blank">1OXM</a></td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>~110 kDa</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Plasma membrane, Postsynaptic density, Synapses</td>
</tr>
<tr>
<td class="label">Family</td>
<td>LDL receptor family (LDLR)</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), [Atherosclerosis](/diseases/atherosclerosis)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/atherosclerosis" style="color:#ef9a9a">Atherosclerosis</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">77 edges</a></td>
</tr>
</table>

LRP8 (ApoER2)

Introduction

...

LRP8 (ApoER2) Protein

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">LRP8 (ApoER2)</th>
</tr>
<tr>
<td class="label">Gene</td>
<td>[LRP8](/genes/lrp8)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9Y6X0" target="_blank">Q9Y6X0</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td><a href="https://www.rcsb.org/structure/1JYH" target="_blank">1JYH</a>, <a href="https://www.rcsb.org/structure/1OXM" target="_blank">1OXM</a></td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>~110 kDa</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Plasma membrane, Postsynaptic density, Synapses</td>
</tr>
<tr>
<td class="label">Family</td>
<td>LDL receptor family (LDLR)</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), [Atherosclerosis](/diseases/atherosclerosis)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/atherosclerosis" style="color:#ef9a9a">Atherosclerosis</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">77 edges</a></td>
</tr>
</table>

LRP8 (ApoER2)

Introduction

LRP8 (also known as ApoER2 or [apolipoprotein E](/proteins/apoe) receptor 2) is a member of the LDL receptor family that plays crucial roles in synaptic function, Reelin signaling, and neuronal migration. It is particularly important in the central nervous system where it mediates signaling events critical for learning, memory, and neuronal plasticity. LRP8 has been implicated in the pathogenesis of Alzheimer's disease and other neurodegenerative disorders[@herz2006].

Pathway / Mechanism Diagram

Mermaid diagram (expand to render)

Overview

LRP8 (ApoER2) is a transmembrane receptor protein belonging to the LDL receptor superfamily. It is highly expressed in the brain, particularly in the [hippocampus](/brain-regions/hippocampus), [cortex](/brain-regions/cortex), and [cerebellum](/brain-regions/cerebellum). LRP8 functions as a receptor for apolipoprotein E (ApoE) isoforms and Reelin, playing essential roles in synaptic plasticity, dendritic spine formation, and neuronal migration during development[@darcangelo1995].

Structure

LRP8 is a type I transmembrane protein with the following structural features:

Domain Architecture

Ligand-binding repeats (LA repeats): Multiple complement-type repeats that bind various ligands including ApoE and Reelin

Epidermal growth factor (EGF) precursor homology domain: Contains EGF-like repeats and β-propeller domains

O-linked sugar domain: Located in the extracellular domain

Transmembrane domain: Single-pass transmembrane helix

Cytoplasmic tail: Contains NPXY motifs for endocytosis and signaling

Key Structural Features

The extracellular domain contains 5-8 ligand-binding repeats depending on alternative splicing
The cytoplasmic tail contains two NPXY motifs that mediate clathrin-mediated endocytosis
LRP8 can form homodimers or heterodimers with other LDLR family members
Alternative splicing produces multiple isoforms with distinct ligand binding properties

Function and Mechanism

Reelin Signaling Pathway

LRP8 is a critical receptor for the extracellular matrix protein Reelin:

Reelin binding to LRP8 activates downstream signaling cascades
Phosphorylation of Disabled-1 (Dab1) and activation of PI3K/Akt pathway
Regulation of cytoskeletal proteins and synaptic spine morphology
Critical for neuronal migration during brain development[@hiesberger1999]

Synaptic Function

LRP8 plays essential roles in synaptic plasticity:

Mediates activity-dependent synaptic modifications
Regulates [NMDA receptor](/entities/nmda-receptor) trafficking and function
Influences [long-term potentiation](/mechanisms/long-term-potentiation) (LTP) and long-term depression (LTD)
Required for proper dendritic spine formation and maintenance[@hoe2009]

Lipid Metabolism

As an ApoE receptor, LRP8 participates in:

Cholesterol homeostasis in the brain
[Aβ](/proteins/amyloid-beta) clearance and metabolism
Lipid transport between [neurons](/entities/neurons) and glia
Modulation of synaptic membrane composition

ApoE Isoform-Specific Effects

LRP8 interacts differentially with ApoE isoforms:

ApoE4 (major AD risk factor) shows reduced binding to LRP8
This differential binding may contribute to ApoE4-associated synaptic deficits
Impaired Reelin signaling in ApoE4 carriers may increase neurodegeneration risk[@huang2012]

Role in Neurodegenerative Diseases

Alzheimer's Disease

LRP8 is implicated in AD pathogenesis through multiple mechanisms:

Aβ metabolism: LRP8 participates in Aβ clearance across the [blood-brain barrier](/entities/blood-brain-barrier)

Synaptic dysfunction: Impaired Reelin-ApoER2 signaling contributes to synaptic deficits

[Tau](/proteins/tau) pathology: LRP8 deficiency may exacerbate tau phosphorylation

Neuroinflammation: Alters inflammatory responses in the brain

Parkinson's Disease

In PD, LRP8 may contribute to:

Dopaminergic neuron survival
[α-Synuclein](/proteins/alpha-synuclein) metabolism and clearance
Mitochondrial function in neurons

Therapeutic Implications

LRP8 represents a potential therapeutic target:

Agonists that enhance LRP8/Reelin signaling may improve synaptic function
Gene therapy approaches to increase LRP8 expression
Small molecules that stabilize LRP8-ApoE interactions
Modulation of LRP8 endocytosis for improved Aβ clearance[@lanedonovan2014]

Key Publications

[Herz & Chen (2006): Reelin signaling directs neuronal positioning](https://pubmed.ncbi.nlm.nih.gov/16641997/)

[D'Arcangelo et al. (1999): Role of Reelin in brain development](https://pubmed.ncbi.nlm.nih.gov/10520937/)

[Hoe et al. (2006): LRP8 mediates ApoE-induced signaling](https://pubmed.ncbi.nlm.nih.gov/16493004/)

[Trommsdorff et al. (1999): LRP8/disabled-1 pathway in neuronal migration](https://pubmed.ncbi.nlm.nih.gov/10558884/)

[May et al. (2004): ApoER2 and synaptic plasticity in the adult brain](https://pubmed.ncbi.nlm.nih.gov/15105522/)

External Links

[PubMed](https://pubmed.ncbi.nlm.nih.gov/)
[KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

References

[Herz J, Chen Y, Reelin, lipoprotein receptors and synaptic plasticity (2006)](https://pubmed.ncbi.nlm.nih.gov/17053810/)

[D'Arcangelo G, Miao GG, Chen SC, et al, A protein related to extracellular matrix proteins deleted in the mouse mutant reeler (1995)](https://pubmed.ncbi.nlm.nih.gov/7715706/)

[Hiesberger T, Trommsdorff M, Howell BW, et al, Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation (1999)](https://pubmed.ncbi.nlm.nih.gov/10571234/)

[Hoe HS, Lee KJ, Carney RS, et al, Engagement of alpha7 nicotinic acetylcholine receptor by endogenous acetylcholine prevents beta-amyloid peptide neurotoxicity (2009)](https://pubmed.ncbi.nlm.nih.gov/19545279/)

[Huang Y, Mucke L, Alzheimer mechanisms and therapeutic strategies (2012)](https://pubmed.ncbi.nlm.nih.gov/22424230/)

[Lane-Donovan C, Philips GT, Herz J, More than cholesterol transporters: lipoprotein receptors in CNS function and neurodegeneration (2014)](https://pubmed.ncbi.nlm.nih.gov/25144875/)

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Related Entities

LRP8APOER2PROTEIN

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kg_node_id	LRP8APOER2PROTEIN
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wiki_page_id	wp-e031892e683e
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-lrp8-apoer2-protein'}
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📊 Evidence Profile Foundational

Evidence Balance

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Certainty

100%

Debates

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Incoming

217

Outgoing

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0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

LRP8 (ApoER2) Protein

LRP8 (ApoER2) Protein

LRP8 (ApoER2)

Introduction

LRP8 (ApoER2) Protein

LRP8 (ApoER2)

Introduction

Pathway / Mechanism Diagram

Overview

Structure

Domain Architecture

Key Structural Features

Function and Mechanism

Reelin Signaling Pathway

Synaptic Function

Lipid Metabolism

ApoE Isoform-Specific Effects

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Therapeutic Implications

Key Publications

See Also

External Links

References

💬 Discussion