Evidence map›Paper›PMID 40551140›Full record

ArticleMolecular neurodegeneration2025

The PKCι-β-arrestin2 axis disrupts SORLA retrograde trafficking, driving its degradation and amyloid pathology in Alzheimer's disease.

Hasibur Rehman, Shun Yan, Shalini Saggu, Mae Aida, Fang Zhang, Yang Shu, Alexis Jones, Amy Trang, Emily Dew, Wenbo Zhi and 5 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular neurodegeneration, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

15 authors.

Hasibur Rehman *Department of Neuroscience and Regenerative Medicine, Medical College of Georgia at Augusta University, 1120 15 Street, Augusta, GA, 30912, USA.
Shun Yan *Center for Biotechnology and Genomic Medicine, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA.
Shalini Saggu *Department of Neuroscience and Regenerative Medicine, Medical College of Georgia at Augusta University, 1120 15 Street, Augusta, GA, 30912, USA.
Mae AidaDepartment of Neuroscience and Regenerative Medicine, Medical College of Georgia at Augusta University, 1120 15 Street, Augusta, GA, 30912, USA.
Fang ZhangDepartment of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
Yang ShuDepartment of Neuroscience and Regenerative Medicine, Medical College of Georgia at Augusta University, 1120 15 Street, Augusta, GA, 30912, USA.
Alexis JonesDepartment of Neuroscience and Regenerative Medicine, Medical College of Georgia at Augusta University, 1120 15 Street, Augusta, GA, 30912, USA.
Amy TrangDepartment of Neuroscience and Regenerative Medicine, Medical College of Georgia at Augusta University, 1120 15 Street, Augusta, GA, 30912, USA.
Emily DewDepartment of Neuroscience and Regenerative Medicine, Medical College of Georgia at Augusta University, 1120 15 Street, Augusta, GA, 30912, USA.
Wenbo ZhiCenter for Biotechnology and Genomic Medicine, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA.
Emily T ClaeboeDepartment of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
Anthony J BaucumDepartment of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
Guangyu WuDepartment of Pharmacology and Toxicology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA.
Kai JiaoCenter for Biotechnology and Genomic Medicine, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA.
Qin WangDepartment of Neuroscience and Regenerative Medicine, Medical College of Georgia at Augusta University, 1120 15 Street, Augusta, GA, 30912, USA. qiwang@augusta.edu.ORCID 0000-0002-1079-5914

Funding

Beta amyloid-adrenergic receptor interaction in Alzheimer's DiseaseR01AG064664 · NIA · UNIVERSITY OF ALABAMA AT BIRMINGHAM · PI WANG, QIN · 2019 to 2024
$2.1M
Regulation of SORLA by beta-arrestin2R01AG067729 · NIA · AUGUSTA UNIVERSITY · PI WANG, QIN · 2024 to 2024
$529k
NIA NIH HHS R01 AG064664NIA NIH HHS R01 AG067729
6 · The paper itself

Abstract

backgroundVariants of SORL1 have been associated with both late and early onset of Alzheimer's disease (AD). SORL1 encodes the sorting-related receptor with A repeat (SORLA) protein, which belongs to the VPS10 receptor family. SORLA protects against AD pathogenesis through its sorting function, and reduced SORLA levels have been consistently observed in sporadic AD. Although the importance of SORLA in AD pathogenesis is well recognized, how it can be targeted for AD treatment remains to be established, owing to the inadequate understanding of its regulation by intracellular signaling.

methodsWe employed combined biochemical, cell biological, and pharmacological approaches to investigate how SORLA trafficking and stability are regulated. Additionally, we used an AD mouse model, postmortem tissue samples, and iPSC-derived neurons to examine the functional outcomes of this regulation.

resultsWe identified a novel direct interaction between SORLA and β-arrestin2 (βARR2), which impedes the interaction of SORLA with the retromer complex, thus reducing the retrograde trafficking of SORLA. βARR2 promotes the interaction between SORLA and the ESCRT0 complex, leading to the lysosomal localization and degradation of SORLA. We also found that PKCι/λ induces SORLA phosphorylation and enhances its interaction with βARR2, promoting SORLA degradation. Importantly, blocking PKCι/λ with auranofin disrupts the SORLA-βARR2 interaction, elevates SORLA levels, decreases amyloidogenic processing of APP, and improves cognition in the App

conclusionOur study reveals the PKCι/λ-βARR2 axis as a key molecular mechanism that disrupts SORLA retrograde trafficking and drives its degradation. Our findings represent the first evidence that SORLA levels can be pharmacologically manipulated through blocking PKCι/λ to reduce Aβ production and alleviate AD-related phenotypes. Notably, repurposing auranofin, an FDA-approved drug for rheumatoid arthritis, may offer the potential for AD treatment.

Indexed as

Alzheimer Diseasebeta-Arrestin 2LDL-Receptor Related ProteinsMembrane Transport ProteinsProtein Kinase CAmyloid beta-PeptidesAnimalsDisease Models, AnimalHumansMiceNeuronsProtein TransportSignal TransductionAmyloid beta-Peptidesbeta-Arrestin 2LDL-Receptor Related ProteinsMembrane Transport ProteinsProtein Kinase CSORL1 protein, humanAlzheimer’s diseaseAβ productionDegradationPKCι/λProtein–protein interactionSORLATraffickingTreatmentβarrestin2

Identifiers

PMID40551140
PMCPMC12186327

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.