Widespread transposable element dysregulation in human aging brains with Alzheimer's disease

Yayan Feng; Xiaoyu Yang; Yuan Hou; Yadi Zhou; James B Leverenz; Charis Eng; Andrew A Pieper; Alison Goate; Yin Shen; Feixiong Cheng

doi:10.1002/alz.14164

Widespread transposable element dysregulation in human aging brains with Alzheimer's disease

Alzheimers Dement. 2024 Nov;20(11):7495-7517. doi: 10.1002/alz.14164. Epub 2024 Oct 2.

Authors

Yayan Feng^{1

2}, Xiaoyu Yang^{1

3}, Yuan Hou^{1

2}, Yadi Zhou^{1

2}, James B Leverenz⁴, Charis Eng^{2

5

6

7}, Andrew A Pieper^{8

9

10

11

12

13}, Alison Goate^{14

15

16}, Yin Shen^{3

17

18}, Feixiong Cheng^{1

2

5

7}

Affiliations

¹ Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
² Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
³ Institute for Human Genetics, University of California, San Francisco, San Francisco, California, USA.
⁴ Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁵ Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
⁶ Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
⁷ Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
⁸ Department of Psychiatry, Case Western Reserve University, Cleveland, Ohio, USA.
⁹ Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.
¹⁰ Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, USA.
¹¹ Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
¹² Department of Neurosciences, Case Western Reserve University, School of Medicine, Cleveland, Ohio, USA.
¹³ Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, Ohio, USA.
¹⁴ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁵ Nash Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁶ Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁷ Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
¹⁸ Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California, USA.

Abstract

Introduction: Transposable element (TE) dysregulation is associated with neuroinflammation in Alzheimer's disease (AD) brains. Yet, TE quantitative trait loci (teQTL) have not been well characterized in human aged brains with AD.

Methods: We leveraged large-scale bulk and single-cell RNA sequencing, whole-genome sequencing (WGS), and xQTL from three human AD brain biobanks to characterize TE expression dysregulation and experimentally validate AD-associated TEs using CRISPR interference (CRISPRi) assays in human induced pluripotent stem cell (iPSC)-derived neurons.

Results: We identified 26,188 genome-wide significant TE expression QTLs (teQTLs) in human aged brains. Subsequent colocalization analysis of teQTLs with AD genetic loci identified AD-associated teQTLs and linked locus TEs. Using CRISPRi assays, we pinpointed a neuron-specific suppressive role of the activated short interspersed nuclear element (SINE; chr11:47608036-47608220) on expression of C1QTNF4 via reducing neuroinflammation in human iPSC-derived neurons.

Discussion: We identified widespread TE dysregulation in human AD brains and teQTLs offer a complementary analytic approach to identify likely AD risk genes.

Highlights: Widespread transposable element (TE) dysregulations are observed in human aging brains with degrees of neuropathology, apolipoprotein E (APOE) genotypes, and neuroinflammation in Alzheimer's disease (AD). A catalog of TE quantitative trait loci (teQTLs) in human aging brains was created using matched RNA sequencing and whole-genome sequencing data. CRISPR interference assays reveal that an upregulated intergenic TE from the MIR family (chr11: 47608036-47608220) suppresses expression of its nearest anti-inflammatory gene C1QTNF4 in human induced pluripotent stem cell-derived neurons.

Keywords: Alzheimer's disease; CRISPR interference; neuroinflammation; transposable element expression quantitative trait loci; transposable elements.

MeSH terms

Aged
Aging* / genetics
Alzheimer Disease* / genetics
Alzheimer Disease* / pathology
Brain* / metabolism
Brain* / pathology
DNA Transposable Elements* / genetics
Female
Genome-Wide Association Study
Humans
Induced Pluripotent Stem Cells* / metabolism
Male
Neurons / metabolism
Quantitative Trait Loci*
Whole Genome Sequencing

Substances

DNA Transposable Elements

Abstract

MeSH terms

Substances

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