Evidence map›Paper›PMID 40964962›Full record

ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2025

Protective mechanisms against Alzheimer's disease in APOE3-Christchurch homozygous astrocytes.

Xinran Tian, Erica Keane Rivera, Inyoung Hwang, Arina A Nikitina, Jennifer A Smith, Youngsuh J Cho, Julia Sala-Jarque, Austin DuBose, Clare Andriola, Toby Gollan-Myers and 1 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing 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

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

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

4 citing papers in PubMed.

  1. Review
  2. Protective mechanisms against Alzheimer's disease in APOE3-Christchurch homozygous astrocytes.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
    Article
  3. Review
  4. Review
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

11 authors.

Xinran TianNeuroscience Research Institute, Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, USA.
Erica Keane RiveraNeuroscience Research Institute, Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, USA.
Inyoung HwangNeuroscience Research Institute, Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, USA.
Arina A NikitinaNeuroscience Research Institute, Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, USA.
Jennifer A SmithBiological Nanostructures Laboratory, University of California Santa Barbara, Santa Barbara, California, USA.
Youngsuh J ChoNeuroscience Research Institute, Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, USA.
Julia Sala-JarqueNeuroscience Research Institute, Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, USA.
Austin DuBoseNeuroscience Research Institute, Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, USA.
Clare AndriolaNeuroscience Research Institute, Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, USA.
Toby Gollan-MyersNeuroscience Research Institute, Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, USA.
Kenneth S KosikNeuroscience Research Institute, Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, USA.

Funding

Molecular Basis of the Tau Aggregation PathwayR01AG056058 · NIA · UNIVERSITY OF CALIFORNIA SANTA BARBARA · PI Songi Han, KENNETH Stephen KOSIK · 2017 to 2026
$6.4M
The complex interaction between Alzheimer drivers and agingRF1AG062479 · NIA · UNIVERSITY OF CALIFORNIA SANTA BARBARA · PI KOSIK, KENNETH STEPHEN · 2020 to 2020
$2.6M
NIA NIH HHS R01 AG056058NIA NIH HHS RF1 AG062479NIH HHS 1RF1AG062479
6 · The paper itself

Abstract

introductionAlzheimer's disease (AD) is characterized by tau pathology, leading to neurodegeneration. Astrocytes regulate central nervous system homeostasis and influence AD progression. The APOE3-Christchurch (APOE3-Ch) variant is linked to AD resilience, but its protective mechanisms remain unclear.

methodsHuman induced pluripotent stem cell-derived astrocytes (APOE3-Ch and wild type) were used to assess tau uptake, clearance, lipid metabolism, and transcriptomic adaptations. Fluorescently labeled 2N4R-P301L tau oligomers were tracked, and pathway-specific inhibitors dissected tau clearance mechanisms. Lipidomic and transcriptomic analyses were performed to identify genotype-specific adaptations.

resultsAPOE3-Ch astrocytes exhibited enhanced tau uptake via heparan sulfate proteoglycan- and lipoprotein receptor-related protein 1-mediated pathways and superior clearance through lysosomal and proteasomal degradation. They exported less tau, limiting propagation. Transcriptomic analyses revealed upregulation of genes involved in cell projection assembly and endocytosis. Lipidomic profiling showed reduced ceramides and gamma-linolenic acid, linked to decreased neuroinflammation and ferroptosis. DISCUSSION: APOE3-Ch astrocytes promote tau clearance and metabolic adaptations, providing insights into genetic resilience in AD and potential therapeutic targets. HIGHLIGHTS: APOE3-Christchurch (APOE3-Ch) astrocytes exhibit significantly increased tau internalization compared to wild-type astrocytes, facilitated by upregulated heparan sulfate proteoglycan and low-density lipoprotein receptor-related protein 1 pathways. APOE3-Ch astrocytes demonstrate more efficient tau degradation via both lysosomal and proteasomal pathways, while exporting significantly less tau, potentially reducing tau propagation in the central nervous system. APOE3-Ch astrocytes show upregulation of genes involved in cell projection assembly and endocytosis, suggesting structural and functional modifications that enhance tau processing. Lipidomic profiling reveals reduced ceramide levels and gamma-linolenic acid downregulation in APOE3-Ch astrocytes, alterations linked to reduced neuroinflammatory and ferroptotic activity, contributing to the protective phenotype.

Indexed as

Alzheimer DiseaseApolipoprotein E3Astrocytestau ProteinsHomozygoteHumansInduced Pluripotent Stem CellsLipid MetabolismApolipoprotein E3tau ProteinsAlzheimer's diseaseAPOE3‐Christchurchendolysosomal traffickingheparan sulfate proteoglycansinduced pluripotent stem cell–derived astrocyteslipid metabolismlipoprotein receptor‐related protein 1lysosomal degradationproteasomal degradationtau oligomerstau pathology

Identifiers

PMID40964962
PMCPMC12444642

What OpenQuestion holds

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Registered trials

None linked

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.