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Establishment of a causal link between AD and L1 retrotransposons

Award Number: R01AG078959
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: 07/31/2027

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Establishment of a causal link between AD and L1 retrotransposons - Abstract Our overall goal is to determine a potential causal link between L1, an active retrotransposon element, in human brain cells and Alzheimer's Disease (AD). L1s are involved in numerous human diseases with different molecular and cellular mechanisms. L1 expression was also found to be upregulated in AD postmortem human tissues, leading to the speculation that L1s could contribute, at least partially, to the mechanisms leading to AD in humans. However, despite all these correlations, there is no experimental-based causal link between L1s and AD so far. Here, we hypothesized that L1 expression in AD-derived brain cells can contribute to AD pathology, using both cell-autonomous and non-cell-autonomous mechanisms. Accumulation of L1-derived ssDNA molecules in the cytoplasm of glial cells might be responsible for a chronic low-level stimulation of the immune system, aka “sterile” inflammation, and can aggravate molecular and cellular phenotypes in neurons derived from AD patients. Moreover, a cell autonomous mechanism, triggered by L1 ssDNA accumulation in neurons could accelerate and exacerbate molecular and cellular phenotypes related to AD pathogenesis. Thus, the combinatory impact of L1 expression in the different cell types could causally contribute to AD. To experimentally test this hypothesis, we will use induced pluripotent stem cells (iPSC) from controls and AD to overexpress L1 ssDNA molecules and analyze their impact on different neuronal types individually or in combination using a brain organoid model system. The use of iPSC-derived cells and organoid model is perfectly suited as we can isolate the aging effect and capture the entire genome of AD individuals in relevant cell types. We have designed the following specific aims to test our hypothesis: Aim 1: Determine the impact of L1 retrotransposons in AD-derived astrocytes. We will measure alterations in transcriptomics, cytokines/interferon release levels and interferon-stimulated gene (ISGs) expression in AD/isogenic-derived astrocytes upon L1 ssDNA overexpression. We will also evaluate neurotoxicity using astrocyte conditioned media from AD-derived astrocytes overexpressing L1 ssDNA. Aim 2: Determine the impact of L1 retrotransposons in AD-derived cortical neurons. We will measure Tau aggregation and phosphorylation, and synaptic loss, all early hallmarks of the AD progression. Aim 3: To model AD progression with a brain organoid model. We will use our optimized protocol to generate brain cortical organoids (BCO) infused with human microglia from AD- and control individuals. BCO with L1 ssDNA but treated with nucleoside reverse transcriptase inhibitors (NRTI) as a protective agent, will be compared. Our proposal aims to demonstrate an eventual causal contribution of L1-derived ssDNA to molecular, cellular and network phenotypes in brain cells and organoids derived from AD individuals. Our data will reveal unexplored pathways with immediate therapeutic relevance that could lead to transformative treatments for AD and other aging-related syndromes.


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 = $766,077 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	4	8/25/2025	NON-COMPETING CONTINUATION	$766,077
														Subtotal = $766,077

Issue Date FY: 2024 ( Subtotal = $783,212 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	3	7/19/2024	NON-COMPETING CONTINUATION	$783,212
														Subtotal = $783,212

Issue Date FY: 2023 ( Subtotal = $784,679 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	001	2	7/11/2023	NON-COMPETING CONTINUATION	$784,679
2023	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	1	11/10/2022	NEW	$0
														Subtotal = $784,679

Issue Date FY: 2022 ( Subtotal = $786,116 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	1	9/13/2022	NEW	$786,116
														Subtotal = $786,116

Grand Total All Awards = $3,120,084

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Establishment of a causal link between AD and L1 retrotransposons

Award Number: R01AG078959

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: 07/31/2027

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