Friday, November 22, 2024
11/22/2024
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
