# Demonstrating interactome-level connections between Alzheimer disease, LINE-1 retrotransposons, and cellular senescence

> **NIH NIH R01** · ROCKEFELLER UNIVERSITY · 2020 · $191,455

## Abstract

Project Summary: Alzheimer's Disease (AD) and AD-related dementias (ADRDs; e.g. Frontotemporal
Dementia, Lewy Body Dementia, etc.) are crippling neurodegenerative disorders. Notably, the onset of these
diseases is strongly correlated with aging. In spite of decades of research and clinical effort, cures for AD and
ADRDs remain elusive. Indeed, Alzheimer's has become the 6th most frequent cause of death in the USA. New
hypotheses and mechanisms for Alzheimer's and ADRDs are urgently needed to guide novel therapeutic
approaches: an emerging candidate contributor to Alzheimer's and ADRD is the LINE-1 retrotransposon, which
becomes deregulated during aging and thus correlates with Alzheimer's / ADRD onset. One hypothetical
mechanism by which LINE-1 may contribute to Alzheimer's / ADRD is through its exacerbation of cellular
senescence. Senescence is a phenomenon by which normal cells stop dividing; these cells accumulate with
advancing age and are found at the locations of dysfunction in age-related diseases. In mice, senescent cells
have been shown to shorten life and actively drive age-related neurodegeneration; preventing senescent cell
accumulation decreases tau-dependent degeneration and cognitive decline. AD patients exhibit increased
indicators of cellular senescence. It is increasingly clear that senescent cells are not inert, but instead drive tissue
deterioration via the senescence-associated secretory phenotype - secreting a variety of growth factors and pro-
inflammatory cytokines. LINE-1 retrotransposons have recently been shown to drive progression of the
senescence-associated secretory phenotype, and thus, LINE-1 is an important agent of cellular senescence.
LINE-1 activation is also associated with AD related Tau pathologies. The LINE-1 encoded ORF2p enzyme
(endonuclease and reverse transcriptase) is often flagged as a source of pathological cellular insults, e.g. via
new, mutagenic LINE-1 insertions and contributions to chromosomal instability. However, the effects of LINE-1
expression extend beyond DNA damage. Numerous mechanisms may be at play, including the titration of
normally homeostatic host factors away from their physiologic functions and into LINE-1 ribonucleoprotein
granules, as well as the production of immunity-and-inflammation-triggering cytoplasmic LINE-1 DNA:RNA
hybrids; indeed, the latter is now understood to be a key component of LINE-1’s role in cellular senescence.
Moreover, LINE-1 also mobilizes Alu and other non-autonomous retrotransposons. Taken all together, LINE-1
is imbued with a prodigious array of opportunities for pathologic interventions in cell function.
We will capture and analyze LINE-1 ribonucleoproteins in senescent cells and Alzheimer's / ADRD afflicted brain
tissues, gathering additional evidence to support or refute the hypothesis that LINE-1 is a causal agent in
Alzheimer's / ADRD.

## Key facts

- **NIH application ID:** 10123395
- **Project number:** 3R01GM126170-03S1
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** John LaCava
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $191,455
- **Award type:** 3
- **Project period:** 2017-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123395

## Citation

> US National Institutes of Health, RePORTER application 10123395, Demonstrating interactome-level connections between Alzheimer disease, LINE-1 retrotransposons, and cellular senescence (3R01GM126170-03S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10123395. Licensed CC0.

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