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Browsing by Subject "Cerebral Amyloid Angiopathy"
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Item The Neuroinflammatory Response Associated to Cerebral Amyloid Angiopathy (CAA)(2021-12) Taylor, Xavier Nathaniel; Kim, Jungsu; Landreth, Gary; Oblak, Adrian; Vidal, Ruben; Lasagna-Reeves, CristianCerebral amyloid angiopathy (CAA) is characterized by the cerebrovascular deposition of amyloid. The mechanisms underlying the contribution of CAA to neurodegeneration are not fully understood. In this dissertation, there are three main chapters. The first chapter investigates existing evidence regarding the amyloid diversity in CAA and its relation to tau pathology and immune response, as well as the possible contribution of molecular and cellular mechanisms, previously associated with parenchymal amyloid in Alzheimer disease (AD) and AD-related dementias, to the pathogenesis of CAA. The second chapter demonstrates differential glial reactivity and activation associated with early-stage CAA in a mouse model of Familial Danish Dementia (FDD), a neurodegenerative disease characterized by vascular accumulation of Danish amyloid (ADan). We show that early-stage CAA is associated with dysregulation in immune response networks and lipid processing, severe astrogliosis with a neurotoxic A1-astrocytic phenotype, characterized by increased expression of Complement Component 3 (C3), and decreased levels of Triggering Receptor Expressed On Myeloid Cells 2 (Trem2) with no significant reactive microgliosis. Our results also indicate how cholesterol accumulation and Apolipoprotein E (ApoE) are associated with vascular amyloid deposits at the early stages of pathology. Furthermore, we demonstrate A1 astrocytic mediation of Trem2 and microglia homeostasis. In the final chapter, we addressed whether inflammatory stimulus of other cell types are capable of inducing a subtype of neurotoxic astrocytes. Here we show a subtype of C3+ neurotoxic astrocyte are induced by activated endothelial cells that is distinct from astrocytes classically activated by microglia. We show that endothelial activated astrocytes have upregulated expression of A1-astrocytic genes and exhibit a distinctive extracellular matrix remodeling profile. Finally, we demonstrate that endothelial activated astrocytes are Decorin-positive and are associated to vascular amyloid deposits but not parenchymal amyloid plaques in mouse models and AD/CAA patients. These findings show the existence of potentially extensive and subtle functional diversity of C3+-reactive astrocytes.Item White matter hyperintensities and the mediating role of cerebral amyloid angiopathy in dominantly-inherited Alzheimer's disease(Public Library of Science, 2018-05-09) Lee, Seonjoo; Zimmerman, Molly E.; Narkhede, Atul; Nasrabady, Sara E.; Tosto, Giuseppe; Meier, Irene B.; Benzinger, Tammie L. S.; Marcus, Daniel S.; Fagan, Anne M.; Fox, Nick C.; Cairns, Nigel J.; Holtzman, David M.; Buckles, Virginia; Ghetti, Bernardino; McDade, Eric; Martins, Ralph N.; Saykin, Andrew J.; Masters, Colin L.; Ringman, John M.; Fӧrster, Stefan; Schofield, Peter R.; Sperling, Reisa A. n; Johnson, Keith A. n; Chhatwal, Jasmeer P.; Salloway, Stephen; Correia, Stephen; Jack, Clifford R., Jr.; Weiner, Michael; Bateman, Randall J.; Morris, John C.; Mayeux, Richard; Brickman, Adam M.; Dominantly Inherited Alzheimer Network; Pathology and Laboratory Medicine, School of MedicineINTRODUCTION: White matter hyperintensity (WMH) volume on MRI is increased among presymptomatic individuals with autosomal dominant mutations for Alzheimer's disease (AD). One potential explanation is that WMH, conventionally considered a marker of cerebrovascular disease, are a reflection of cerebral amyloid angiopathy (CAA) and that increased WMH in this population is a manifestation of this vascular form of primary AD pathology. We examined whether the presence of cerebral microbleeds, a marker of CAA, mediates the relationship between WMH and estimated symptom onset in individuals with and without autosomal dominant mutations for AD. PARTICIPANTS AND METHODS: Participants (n = 175, mean age = 41.1 years) included 112 with an AD mutation and 63 first-degree non-carrier controls. We calculated the estimated years from expected symptom onset (EYO) and analyzed baseline MRI data for WMH volume and presence of cerebral microbleeds. Mixed effects regression and tests of mediation were used to examine microbleed and WMH differences between carriers and non-carriers and to test the whether the association between WMH and mutation status is dependent on the presence of microbleeds. RESULTS: Mutation carriers were more likely to have microbleeds than non-carriers (p<0.05) and individuals with microbleeds had higher WMH volume than those without (p<0.05). Total WMH volume was increased in mutation carriers compared with non-carriers, up to 20 years prior to EYO, after controlling for microbleed status, as we demonstrated previously. Formal testing of mediation demonstrated that 21% of the association between mutation status and WMH was mediated by presence of microbleeds (p = 0.03) but a significant direct effect of WMH remained (p = 0.02) after controlling for presence of microbleeds. DISCUSSION: Although there is some co-dependency between WMH and microbleeds, the observed increases in WMH among mutation carriers does not appear to be fully mediated by this marker of CAA. The findings highlight the possibility that WMH represent a core feature of AD independent of vascular forms of beta amyloid.