Research reveals how transposable elements in Alzheimer’s-affected brains could hold the key to new therapeutic approaches, as scientists uncover the genetic links behind these molecular disruptions.
Study: Widespread dysregulation of transposable elements in aging brains of people with Alzheimer’s disease. Image credits: Tushchakorn / Shutterstock.com
A recent one Alzheimer’s and dementia journal study characterizes dysregulation of transposable element (TE) expression using CRISPR interference (CRISPRi) assays to experimentally identify TEs associated with Alzheimer’s disease (AD).
What are TEs?
TEs, also known as transposons, viral elements or jumping genes, make up about 45% of the human genome. Epigenetic mechanisms, such as histone modifications and DNA methylation, can transcriptionally silence TEs.
The functional significance of TEs decreases significantly with aging and in patients with neurodegenerative diseases, such as AD. Previous studies using human postmortem brain tissue Drosophila melanogaster models have reported that tau protein causes TE activation, which is linked to active chromatin signatures at multiple endogenous retrovirus (ERV) genomic loci.
TE activation is also crucial during neurological development, suggesting that TE regulation in the brain is a common feature throughout the human lifespan. During mouse brain development, higher ERV levels in neurons have been associated with inflammatory responses and activated microglia.
Depression of families with long terminal repeats (LTR) and a panel of long interspersed nuclear elements (LINEs) leads to degenerative phenotypes in human TDP-43 Drosophila neurons and glia, which can be rescued by blocking TE expression. Therefore, aging-related brain disorders can also be treated by therapeutically targeting TEs.
Thus, it is critical to better understand the mechanisms involved in TE dysregulation in the aging human brain.
About the study
TE expression and dysregulation in multiple AD pathologies were analyzed using two complementary approaches. Ribonucleic acid (RNA) sequencing (RNA-seq) data were obtained from three brain biobanks, including the Mount Sinai Brain Bank (MSBB), Mayo Clinic (Mayo), and Religious Orders Study (ROS) or Rush Memory and Aging Project (MAP). ) (ROS/CARD). TE transcription profiles with matched whole genome sequencing (WGS) data were hypothesized to identify genes responsible for controlling TE expression.
Findings of the study
A total of 26,188 genome-wide significant TE-mediated quantitative trait loci (teQTLs) were identified in human brain. To isolate risk loci associated with TE dysregulation, colocalization analysis was performed using AD genome-wide association study (GWAS) datasets containing DNA methylation QTLs (meQTLs), teQTLs, gene expression QTLs (eQTLs), and H3K27 histone acetylation -QTLs (haQTLs) .
Human brain cell type-specific enhancer-promoter interactome maps and CRISPRi assays were performed on human induced pluripotent stem cell (iPSC)-derived excitatory neurons. These assays were used to determine the regulatory relationship between an upregulated TE and its potential target gene. C1QTNF4, and short alternating core element (SINE).
Dysregulation of TE in AD was associated with amyloid neuropathology, tau pathology, and apolipoprotein ε4 (APOE ε4) genotypes. This dysregulation was both sex- and cell-specific.
The colocalization analysis revealed that upregulation in TEs was associated with changes in gene expression, including C1QTNF4, bfound in human iPSC-derived neurons from AD patients. These findings highlight the effectiveness of QTL as an analytical tool to detect TE-related risk genes in AD.
AMP-AD RNA-seq harmonization was used to maintain clinical heterogeneity between samples. This approach enabled the identification of highly reproducible, locus-based and region-specific, differentially expressed TEs between both Mayo and ROS/MAP brain biobanks.
ERV1 was significantly downregulated in MSBB and ROS/MAP biobanks. However, the overexpression of LINE-1 and ERVs was observed in both Mayo and ROS/MAP brain biobank samples. Chronological ordination analysis of LINE-1 subfamily TEs indicated that L1HS, L1PA, and L1PB are more sensitive in aging brains with AD.
Consistent with previous reports, the current study observed a decrease in TE expression in aging AD brains. Decreased TE activity can also affect the host immune response.
The number of locus-based differentially expressed TEs was proportional to the sequencing read length (MSBB). Notably, longer sequencing reads, such as Oxford nanopore sequencing reads, could allow the generation of additional TE transcripts.
RNA-seq data from fluorescence-activated cell sorting (FACS)-sorted cell types using frozen brain cell samples indicated a APOE ε4-specific TE activation from a SINE in microglia. The experimental findings also highlight the possible role of TEs in sex-specific gene regulatory networks.
Conclusions
The current study identified widespread TE dysregulation in human aging brains with AD. Activated TE can produce double-stranded RNA (dsRNA), small RNAs (sRNAs), interfering RNAs, and P-element-induced Wimpy testis (PIWI)-interacting RNAs (piRNAs), which can affect nearby genes associated with the inflammatory response.
To determine the precise functional role of TEs in the future, biological mechanisms involved in TE activation, chromatin changes, and dysregulation of target genes need to be identified.
Magazine reference:
- Feng, Y., Yang, X., Hou, Y., et al. (2024) Widespread dysregulation of transposable elements in aging brains of people with Alzheimer’s disease. Alzheimer’s and dementia. doi:10.1002/alz.14164