PhD Public Seminar: ROMEESA KHAN
When & Where
November 10
2:00 PM - 3:00 PM
Contact
- Joy A. Lademora
- 713-500-5072
- [email protected]
Event Description
Ischemic Stroke as a Chronic, Neurodegenerative Disease: Neuroinflammation, Senescence, and Therapeutic Opportunity
Romeesa Khan (Advisor: Louise McCullough, MD, PhD)
Stroke is the fourth leading cause of death and the leading cause of long-term disability in the US. Although advancements in acute treatment have increased stroke survival rates, more than half of all stroke survivors live with some degree of cognitive impairment. About 50% of people with post-stroke cognitive impairment (PSCI) are diagnosed with vascular cognitive impairment (VCI), and post-stroke dementia (PSD) may result from both VCI and degenerative pathologies. This dissertation tests the hypothesis that ischemic stroke sets off long-lasting, continuous, secondary injury cascades that lead to chronic oxidative stress, inflammation, and cellular dysfunction, immune senescence, and blood-brain-barrier (BBB) dysfunction. By demonstrating that various secondary mechanisms could be driving PSCI, and that these mechanisms are targetable, I further test the idea that stroke can be treated outside of the current treatment window of a few hours.
Using transient middle cerebral artery occlusion (tMCAO) in young and aged mice of both sexes, followed for up to six months, I found that stroke caused cognitive impairment that worsened over time, persistent depressive-like behavior, progressive brain atrophy, chronic gliosis and neuronal apoptosis, and senescence-like microglia with lysosomal and lipid accumulation. Bulk transcriptomics at six months showed sustained activation of inflammatory, apoptotic, and complement pathways. Postmortem human brain tissue with chronic infarcts showed the same features in the hippocampus, far from the lesion, together with demyelination and increased Aβ42. IgG extravasation and collagen deposition increased from one to six months, indicating delayed fibrosis and lasting barrier failure.
Repeated infusion of plasma from chronic-stroke mice into young wild-type mice caused thymic atrophy, impaired neutrophil function, expansion and senescence of bone marrow progenitors, pro-inflammatory and senescence-like microglia, and deficits in recognition memory and fear learning. Delayed treatment with the senolytic combination dasatinib and quercetin (D+Q), started one month after stroke, reduced astrogliosis and hippocampal microglial activation, and improved spatial memory and associative learning. Finally, transcriptomics identified matrix metalloproteinase-12 (MMP12) as a chronic-phase candidate; MMP12 activity was elevated in human postmortem hippocampus and cerebrospinal fluid, and delayed inhibition with Aderamastat (FP-025) significantly improved motor and cognitive performance in mice after treatment, and treatment also reduced the extent of BBB dysfunction and fibrotic changes in the brain.
Together, these findings show that ischemic stroke behaves as a chronic, progressive neurodegenerative disease that accelerates brain aging through linked central and systemic mechanisms. Cellular senescence and MMP12, and BBB dysfunction, emerge as major drivers and targets of chronic post-stroke pathology, that can be treated long after the acute window has closed—providing hope for stroke survivors living with PSCI.
Advisory Committee:
- Louise McCullough, MD, PhD, Chair
- Rodney Ritzel, Co-Chair
- Kevin Lin, PhD
- Pamela Wenzel, PhD
- Long-Jun Wu, PhD
Ischemic Stroke as a Chronic, Neurodegenerative Disease: Neuroinflammation, Senescence, and Therapeutic Opportunity
Romeesa Khan (Advisor: Louise McCullough, MD, PhD)
Stroke is the fourth leading cause of death and the leading cause of long-term disability in the US. Although advancements in acute treatment have increased stroke survival rates, more than half of all stroke survivors live with some degree of cognitive impairment. About 50% of people with post-stroke cognitive impairment (PSCI) are diagnosed with vascular cognitive impairment (VCI), and post-stroke dementia (PSD) may result from both VCI and degenerative pathologies. This dissertation tests the hypothesis that ischemic stroke sets off long-lasting, continuous, secondary injury cascades that lead to chronic oxidative stress, inflammation, and cellular dysfunction, immune senescence, and blood-brain-barrier (BBB) dysfunction. By demonstrating that various secondary mechanisms could be driving PSCI, and that these mechanisms are targetable, I further test the idea that stroke can be treated outside of the current treatment window of a few hours.
Using transient middle cerebral artery occlusion (tMCAO) in young and aged mice of both sexes, followed for up to six months, I found that stroke caused cognitive impairment that worsened over time, persistent depressive-like behavior, progressive brain atrophy, chronic gliosis and neuronal apoptosis, and senescence-like microglia with lysosomal and lipid accumulation. Bulk transcriptomics at six months showed sustained activation of inflammatory, apoptotic, and complement pathways. Postmortem human brain tissue with chronic infarcts showed the same features in the hippocampus, far from the lesion, together with demyelination and increased Aβ42. IgG extravasation and collagen deposition increased from one to six months, indicating delayed fibrosis and lasting barrier failure.
Repeated infusion of plasma from chronic-stroke mice into young wild-type mice caused thymic atrophy, impaired neutrophil function, expansion and senescence of bone marrow progenitors, pro-inflammatory and senescence-like microglia, and deficits in recognition memory and fear learning. Delayed treatment with the senolytic combination dasatinib and quercetin (D+Q), started one month after stroke, reduced astrogliosis and hippocampal microglial activation, and improved spatial memory and associative learning. Finally, transcriptomics identified matrix metalloproteinase-12 (MMP12) as a chronic-phase candidate; MMP12 activity was elevated in human postmortem hippocampus and cerebrospinal fluid, and delayed inhibition with Aderamastat (FP-025) significantly improved motor and cognitive performance in mice after treatment, and treatment also reduced the extent of BBB dysfunction and fibrotic changes in the brain.
Together, these findings show that ischemic stroke behaves as a chronic, progressive neurodegenerative disease that accelerates brain aging through linked central and systemic mechanisms. Cellular senescence and MMP12, and BBB dysfunction, emerge as major drivers and targets of chronic post-stroke pathology, that can be treated long after the acute window has closed—providing hope for stroke survivors living with PSCI.
Advisory Committee:
- Louise McCullough, MD, PhD, Chair
- Rodney Ritzel, Co-Chair
- Kevin Lin, PhD
- Pamela Wenzel, PhD
- Long-Jun Wu, PhD