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Defining molecular contributions of LINE-1 retrotransposons to AD / ADRD

Award Number: R01AG078925
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Defining molecular contributions of LINE-1 retrotransposons to AD / ADRD - Project Summary: Alzheimer's Disease (AD) and AD-related dementias (ADRDs; e.g. Frontotemporal Dementia, Lewy Body Dementia, etc.) are crippling neurodegenerative disorders. The onset of these diseases is strongly correlated with aging. Cures for AD and ADRDs remain elusive; Alzheimer's has become the 6th most frequent cause of death in the USA. An emerging candidate contributor to Alzheimer's and ADRD is the L1 retrotransposon, which becomes dysregulated during aging and correlates with Alzheimer's / ADRD onset. One hypothetical mechanism by which L1 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. L1 retrotransposons have recently been shown to drive progression of the senescence- associated secretory phenotype, and thus, L1 is an important agent of cellular senescence. L1 activation is also associated with AD-related Tau pathologies. The L1 encoded ORF2p enzyme (endonuclease and reverse transcriptase) is often flagged as a source of pathological cellular insults, e.g. via new, mutagenic L1 insertions and contributions to chromosomal instability. However, the effects of L1 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 L1 ribonucleoprotein granules, as well as the production of immunity-and-inflammation-triggering cytoplasmic L1 DNA:RNA hybrids; indeed, the latter is now understood to be a key component of L1’s role in cellular senescence. Moreover, L1 also mobilizes Alu and other non- autonomous retrotransposons. Objectives: In Aim 1, we will use targeted mass spectrometry to profile L1 ORF1 protein expression in the cerebrospinal fluid (CSF) and post-mortem brain tissues of patients exhibiting AD/ADRD and cognitive decline, as well as in senescent cells and neuronal iPSCs; in Aim 2 (in vitro cell culture) and Aim 3 (clinical samples) we will profile L1-associated protein-protein and protein-RNA interactions in the same biological samples as Aim 1; and in Aim 4 we will take a candidate-based approach using molecular genetics to dissect the mechanisms of action of L1 in senescent cells.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $731,293 )
2025	2025	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	4	5/6/2025	NON-COMPETING CONTINUATION	$671,597
2025	2025	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	001	4	9/5/2025	NON-COMPETING CONTINUATION	$59,696
														Subtotal = $731,293

Issue Date FY: 2024 ( Subtotal = $746,218 )
2024	2024	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	3	5/15/2024	NON-COMPETING CONTINUATION	$746,218
														Subtotal = $746,218

Issue Date FY: 2023 ( Subtotal = $746,218 )
2023	2023	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	2	5/12/2023	NON-COMPETING CONTINUATION	$746,218
														Subtotal = $746,218

Issue Date FY: 2022 ( Subtotal = $779,909 )
2022	2022	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	1	9/9/2022	NEW	$779,909
														Subtotal = $779,909

Grand Total All Awards = $3,003,638

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Defining molecular contributions of LINE-1 retrotransposons to AD / ADRD

Award Number: R01AG078925

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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