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Cellular senescence and Alzheimer's disease

Award Number: R01AG068296
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Cellular senescence and Alzheimer's disease - PROJECT SUMMARY / ABSTRACT Senescent cells develop a senescence-associated secretory phenotype (SASP) involving pro-inflammatory and pro-oxidative factors that can elicit deleterious paracrine-like effects on neighboring cells. Independently of the original stressor, senescence can also spread from senescent to non-senescent bystander cells in a process known as senescence-induced senescence (SIS). Neurons were historically considered to be unable to undergo cellular senescence. Recent research has however provided evidence that neurons may be able to undergo senescence during normal aging and disease. Senolytic drugs, which selectively kill senescent cells, have for example been shown to improve functions in the brains of animal models of Alzheimer’s disease (AD) and related dementias. This new approach is of great importance—clinical trials investing efficacy of amyloid beta (Aβ) antibodies have led to disappointing failures and no known disease-modifying treatments have to date been identified. There is however a caveat to the use of senolytics for AD and related disorders. It is not known whether senolytics kill senescent glial cells and spare neurons because they cannot senesce, or if senolytics not only kill senescent glial cells but also senescent neurons. Senescent cells in the periphery are normally removed by immune cells including natural killer (NK) cells. Due to its unique immune privilege, senescent cells in the brain may initially be able to evade removal by NK cells, allowing for an increase and spread in the overall senescent cell load. When immune privilege becomes compromised in later stages of the disease, this could result in a large-scale removal of senescent cells including neurons. It is unclear whether this would be beneficial or detrimental to global brain health. We will initially assess neuronal senescence in mixed primary human neuronal-astrocytic 2D and 3D cultures recently generated by our laboratory in response to Abeta-mediated stress. We will then determine the role of senescence in vivo utilizing a well-characterized AD mouse model, the 3xTg AD line. This line has been crossed with a p16-3MR transgenic mouse model that allows the identification and inducible ablation of senescent cells. Use of these models will allow us to determine: (1) the ability of neurons, astrocytes, and other CNS cell types to undergo stress-mediated senescence and a SASP, (2) whether this is accompanied by an Abeta-independent SIS, (3) whether late-stage losses in immune privilege enables clearance of senescent cells via infiltration of peripheral immune cells, and (4) whether senescent cell removal is beneficial or detrimental and at what stage of disease progression.


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 = $31,860 )
2025	2024	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	2	3/12/2025	EXTENSION WITH OR WITHOUT FUNDS	$31,860
														Subtotal = $31,860

Issue Date FY: 2024 ( Subtotal = $467,034 )
2024	2024	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	2	7/26/2024	EXTENSION WITH OR WITHOUT FUNDS	$467,034
														Subtotal = $467,034

Grand Total All Awards = $498,894

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Cellular senescence and Alzheimer's disease

Award Number: R01AG068296

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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