Senolytic Therapy Using ABT-263 Reduces Astrocytic Senescence in an Α-Synuclein-Mediated Parkinson’s Disease Model
Faculty Mentor Information
Dr. Yonghwan Kim, Boise State University
Presentation Date
7-16-2026
Abstract
Emerging evidence suggests that cellular senescence (CS) contributes to the progression of neurodegenerative diseases, including Parkinson's disease (PD). Cellular senescence is a state in which cells cease to proliferate in response to damage and contribute to tissue dysfunction through the release of toxic cytokines, collectively termed the Senescence-Associated Secretory Phenotype (SASP). While dopaminergic neurons are the primary cell type lost in the substantia nigra compacta (SNc) in PD, senescent glia—particularly astrocytes—are considered to mediate secondary toxicity that drives neuronal death. Using pre-formed fibrils (PFF) of α-synuclein to induce PD-like pathology, we examined the impact of senolytic (ABT-263) treatment on senescent glial burden and downstream neuroprotection. Cellular senescence was assessed through established markers using immunohistochemistry (IHC) and Western blot analyses. Using triple labelling immunohistochemistry (IHC) and confocal microscopy, we quantified GFAP-positive astrocytes, in addition to the complement protein C3 and the cyclin-dependent kinase inhibitor p21 as markers of reactive or senescent astrocyte states, respectively. In our well-established classification model: GFAP+/C3+/p21- astrocytes are defined as reactive, GFAP+/C3-/p21+ as senescent, GFAP+/C3+/p21+ as ambiguous/transitionary, and GFAP+/C3-/p21- as healthy. PFF injection significantly elevated both C3 and p21 levels in the striatum, cortex, and substantia nigra, while it increased colocalization of C3 and p21 within astrocytes, indicating a shift toward transitionary and senescent states. Oral ABT-263 treatment, reduced both C3 and p21 levels and decreased C3/p21 colocalization in astrocytes, suggesting a reduction in the transitionary and senescent astrocyte populations. These changes were accompanied by significant prevention or reversal of dopaminergic neuronal loss in PFF-injected brains, as verified by IHC. Taken together, these findings demonstrate that PFF-induced PD-like pathology promotes astrocyte dysfunction across a spectrum from reactive to senescent states, and that senolytic clearance of senescent astrocytes attenuates nigrostriatal neurodegeneration. Although our simplified astrocyte classification model may not fully characterize the type of damaged astrocytes, it may offer an approachable method for quantifying glial pathology in PD and Dementia with Lewy body (DLB). These results support that removal of senescent glia as a novel therapeutic strategy that may slow neurodegeneration and pathological progression in human PD patients.
Senolytic Therapy Using ABT-263 Reduces Astrocytic Senescence in an Α-Synuclein-Mediated Parkinson’s Disease Model
Emerging evidence suggests that cellular senescence (CS) contributes to the progression of neurodegenerative diseases, including Parkinson's disease (PD). Cellular senescence is a state in which cells cease to proliferate in response to damage and contribute to tissue dysfunction through the release of toxic cytokines, collectively termed the Senescence-Associated Secretory Phenotype (SASP). While dopaminergic neurons are the primary cell type lost in the substantia nigra compacta (SNc) in PD, senescent glia—particularly astrocytes—are considered to mediate secondary toxicity that drives neuronal death. Using pre-formed fibrils (PFF) of α-synuclein to induce PD-like pathology, we examined the impact of senolytic (ABT-263) treatment on senescent glial burden and downstream neuroprotection. Cellular senescence was assessed through established markers using immunohistochemistry (IHC) and Western blot analyses. Using triple labelling immunohistochemistry (IHC) and confocal microscopy, we quantified GFAP-positive astrocytes, in addition to the complement protein C3 and the cyclin-dependent kinase inhibitor p21 as markers of reactive or senescent astrocyte states, respectively. In our well-established classification model: GFAP+/C3+/p21- astrocytes are defined as reactive, GFAP+/C3-/p21+ as senescent, GFAP+/C3+/p21+ as ambiguous/transitionary, and GFAP+/C3-/p21- as healthy. PFF injection significantly elevated both C3 and p21 levels in the striatum, cortex, and substantia nigra, while it increased colocalization of C3 and p21 within astrocytes, indicating a shift toward transitionary and senescent states. Oral ABT-263 treatment, reduced both C3 and p21 levels and decreased C3/p21 colocalization in astrocytes, suggesting a reduction in the transitionary and senescent astrocyte populations. These changes were accompanied by significant prevention or reversal of dopaminergic neuronal loss in PFF-injected brains, as verified by IHC. Taken together, these findings demonstrate that PFF-induced PD-like pathology promotes astrocyte dysfunction across a spectrum from reactive to senescent states, and that senolytic clearance of senescent astrocytes attenuates nigrostriatal neurodegeneration. Although our simplified astrocyte classification model may not fully characterize the type of damaged astrocytes, it may offer an approachable method for quantifying glial pathology in PD and Dementia with Lewy body (DLB). These results support that removal of senescent glia as a novel therapeutic strategy that may slow neurodegeneration and pathological progression in human PD patients.