Evidence mapPaperPMID 40319306Full record

ArticleMolecular neurodegeneration2025

Alzheimer's disease protective allele of Clusterin modulates neuronal excitability through lipid-droplet-mediated neuron-glia communication.

Xiaojie Zhao, Yan Li, Siwei Zhang, Ari Sudwarts, Hanwen Zhang, Alena Kozlova, Matthew J Moulton, Lindsey D Goodman, Zhiping P Pang, Alan R Sanders and 3 more

Abstract read
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 9 papers.

0numbers the graph read from it
0cells of the map it votes in
9citing 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

9 citing papers in PubMed.

  1. Article
  2. Article
  3. Review
  4. Review
  5. Article
  6. PreoperativeFrontiers in bioinformatics · 2026
    Review
  7. Article
  8. Article
  9. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

13 authors.

Xiaojie ZhaoCenter for Psychiatric Genetics, Endeavor Health, Evanston, IL, 60201, USA.
Yan LiDepartment of Bioinformatics, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
Siwei ZhangCenter for Psychiatric Genetics, Endeavor Health, Evanston, IL, 60201, USA.
Ari SudwartsByrd Alzheimer's Center and Research Institute, University of South Florida, Tampa, FL, 33613, USA.
Hanwen ZhangCenter for Psychiatric Genetics, Endeavor Health, Evanston, IL, 60201, USA.
Alena KozlovaCenter for Psychiatric Genetics, Endeavor Health, Evanston, IL, 60201, USA.
Matthew J MoultonJan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, 77030, USA.
Lindsey D GoodmanJan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, 77030, USA.
Zhiping P PangDepartment of Neuroscience and Cell Biology, Johnson Medical School, Child Health Institute of New Jersey, Rutgers Robert Wood, New Brunswick, NJ, 08901, USA.
Alan R SandersCenter for Psychiatric Genetics, Endeavor Health, Evanston, IL, 60201, USA.
Hugo J BellenJan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, 77030, USA.
Gopal ThinakaranByrd Alzheimer's Center and Research Institute, University of South Florida, Tampa, FL, 33613, USA.
Jubao DuanCenter for Psychiatric Genetics, Endeavor Health, Evanston, IL, 60201, USA. jduan@uchicago.edu.ORCID 0000-0002-7215-3220

Funding

Functional Genomic Dissection of Alzheimer's Disease in Humans and Drosophila ModelsU01AG072439 · BAYLOR COLLEGE OF MEDICINE · 2025 to 2025
$1.6M
Systematic Functional Interpretation of Regulatory Variants in Neuropsychiatric DisordersR01MH106575 · NIMH · ENDEAVOR HEALTH CLINICAL OPERATIONS · 2023 to 2025
$1.4M
Microglial function of GWAS risk factor BIN1 in Alzheimer's disease pathogenesis and inflammatory signalingR01AG079141 · UNIVERSITY OF SOUTH FLORIDA · 2025 to 2025
$709k
Neuronal Vulnerability to Lipid Droplets and Cholesterol in Alzheimer's DiseaseR01AG081374 · ENDEAVOR HEALTH CLINICAL OPERATIONS · 2025 to 2025
$669k
Integrating epigenomics with DNA breathing dynamics for human non-coding disease variantsR01MH116281 · NIMH · ENDEAVOR HEALTH CLINICAL OPERATIONS · PI Boian Stoianov Alexandrov, Jubao Duan · 2022 to 2022
$598k
IMPACTS OF GLIAL LIPID DROPLETS ON OXIDATIVE STRESS AND NEURODEGENERATION IN ALZHEIMER'S DISEASER01AG073260 · BAYLOR COLLEGE OF MEDICINE · 2025 to 2025
$447k
National Institute of Mental Health and Neurosciences R01MH106575National Institute of Mental Health and Neurosciences R01MH116281NIA NIH HHS R01 AG063175NIA NIH HHS R01AG063175NIA NIH HHS R01 AG073260NIA NIH HHS R01 AG079141NIA NIH HHS R01 AG081374NIA NIH HHS R01AG081374NIA NIH HHS RF1 AG079141NIA NIH HHS RF1AG079141NIA NIH HHS U01 AG072439NIMH NIH HHS R01 MH106575NIMH NIH HHS R01 MH116281
6 · The paper itself

Abstract

backgroundGenome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified a plethora of risk loci. However, the disease variants/genes and the underlying mechanisms have not been extensively studied.

methodsBulk ATAC-seq was performed in induced pluripotent stem cells (iPSCs) differentiated various brain cell types to identify allele-specific open chromatin (ASoC) SNPs. CRISPR-Cas9 editing generated isogenic pairs, which were then differentiated into glutamatergic neurons (iGlut). Transcriptomic analysis and functional studies of iGlut co-cultured with mouse astrocytes assessed neuronal excitability and lipid droplet formation.

resultsWe identified a putative causal SNP of CLU that impacted neuronal chromatin accessibility to transcription-factor(s), with the AD protective allele upregulating neuronal CLU and promoting neuron excitability. And, neuronal CLU facilitated neuron-to-glia lipid transfer and astrocytic lipid droplet formation coupled with reactive oxygen species (ROS) accumulation. These changes caused astrocytes to uptake less glutamate thereby altering neuron excitability.

conclusionsFor a strong AD-associated locus near Clusterin (CLU), we connected an AD protective allele to a role of neuronal CLU in promoting neuron excitability through lipid-mediated neuron-glia communication. Our study provides insights into how CLU confers resilience to AD through neuron-glia interactions.

Indexed as

Alzheimer DiseaseCell CommunicationClusterinLipid DropletsNeurogliaNeuronsAllelesAnimalsAstrocytesGenome-Wide Association StudyHumansInduced Pluripotent Stem CellsMicePolymorphism, Single NucleotideClusterinAllele-specific open chromatinAlzheimer’s diseaseClusterinGenome-wide association studyIPSCLipid dropletsNeuron excitabilityNeuron-glia lipid transferProtective allele

Identifiers

PMID40319306
PMCPMC12049787

What Socratic holds

Textmetadata
LicenceCC BY
Read underepoch 390

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 Socratic graph.