A retrotransposon storm marks clinical phenoconversion to late-onset Alzheimer’s disease

Abstract

Recent reports have suggested that the reactivation of otherwise transcriptionally silent transposable elements (TEs) might induce brain degeneration, either by dysregulating the expression of genes and pathways implicated in cognitive decline and dementia or through the induction of immune-mediated neuroinflammation resulting in the elimination of neural and glial cells. In the work we present here, we test the hypothesis that differentially expressed TEs in blood could be used as biomarkers of cognitive decline and development of AD. To this aim, we used a sample of aging subjects (age > 70) that developed late-onset Alzheimer’s disease (LOAD) over a relatively short period of time (12–48 months), for which blood was available before and after their phenoconversion, and a group of cognitive stable subjects as controls. We applied our developed and validated customized pipeline that allows the identification, characterization, and quantification of the differentially expressed (DE) TEs before and after the onset of manifest LOAD, through analyses of RNA-Seq data. We compared the level of DE TEs within more than 600,000 TE-mapping RNA transcripts from 25 individuals, whose specimens we obtained before and after their phenotypic conversion (phenoconversion) to LOAD, and discovered that 1790 TE transcripts showed significant expression differences between these two timepoints (logFC ± 1.5, logCMP > 5.3, nominal p value < 0.01). These DE transcripts mapped both over- and under-expressed TE elements. Occurring before the clinical phenoconversion, this TE storm features significant increases in DE transcripts of LINEs, LTRs, and SVAs, while those for SINEs are significantly depleted. These dysregulations end with signs of manifest LOAD. This set of highly DE transcripts generates a TE transcriptional profile that accurately discriminates the before and after phenoconversion states of these subjects. Our findings suggest that a storm of DE TEs occurs before phenoconversion from normal cognition to manifest LOAD in risk individuals compared to controls, and may provide useful blood-based biomarkers for heralding such a clinical transition, also suggesting that TEs can indeed participate in the complex process of neurodegeneration.

A pilot study to investigate the safety and feasibility of antiretroviral therapy for Alzheimer’s disease (ART-AD)

“…Transcriptional analyses of post-mortem human brain identify retrotransposon-encoded transcripts, particularly of the “endogenous retrovirus” class, that are elevated in Alzheimer’s disease and progressive supranuclear palsy, a “primary” tauopathy 7 , and suggest that such activation is a consequence of pathogenic forms of tau 10 . In line with these findings, longitudinal analysis of blood isolated from patients with Alzheimer’s disease further reveals a significant increase in retrotransposon transcripts prior to phenoconversion from normal cognition to cognitive impairment 21 . Work in model organisms of tauopathy further demonstrate that retrotransposon activation is a causal factor driving neurodegeneration and neuroinflammation 7,11,12,22,23 .…”

The reverse transcriptase inhibitor 3TC protects against age‐related cognitive dysfunction

“…Collectively, these observations support the idea that brain aging is associated with a broad dysregulation of TE transcripts, including numerous retrotransposons that could have deleterious effects, and that these events may be: (1) further exacerbated in Alzheimer's disease, perhaps by tau as others have reported in mice (Ramirez et al, 2022); and (2) involved in age-associated cognitive decline and neurodegeneration independent of pathology. (Macciardi et al, 2022), and 3TC is a clinically translatable drug that has been FDA-approved for over 25 years (Grodeck & Vazquez, 1997). In fact, several ongoing clinical trials (NCT04552795, NCT04500847 and NCT04993768) are assessing the safety and effects of 3TC and other reverse transcriptase inhibitors in Alzheimer's disease and other tauopathies (Macedo et al, 2022).…”

Nanopore-based DNA long-read sequencing analysis of the aged human brain

“…We extended our analyses to determine if the number of retrotransposon insertions differs based on Braak stage. The upregulation of retrotransposon transcripts in Alzheimer's disease and progressive supranuclear palsy, along with increased transposition in a Drosophila model of tauopathy suggest that transposable elements may mobilize in human Alzheimer's disease [11,48,49,[95][96][97][98]. While our finding that potentially somatic insertion rates were not significantly different between human brains at Braak 0, Braak III, and Braak V/VI, we do find that two individuals at Braak V/VI have elevated insertions compared to other groups.…”