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Sickle cell disease mice have cerebral oxidative stress and vascular and white matter abnormalities.

ABSTRACT: Strokes are feared complications of sickle cell disease (SCD) and yield significant neurologic and neurocognitive deficits. However, even without detectable strokes, SCD patients have significant neurocognitive deficits in domains of learning and memory, processing speed and executive function. In these cases, mechanisms unrelated to major cerebrovascular abnormalities likely underlie these deficits. While oxidative stress and stress-related signaling pathways play a role in SCD pathophysiology, their role in cerebral injury remains unknown. We have shown that Townes and BERK SCD mice, while not having strokes, recapitulate neurocognitive deficits reported in humans. We hypothesized that cognitive deficits in SCD mice are associated with cerebral oxidative stress. We showed that SCD mice have increased levels of reactive oxygen species, protein carbonylation, and lipid peroxidation in hippocampus and cortex, thus suggesting increased cerebral oxidative stress. Further, cerebral oxidative stress was associated with caspase-3 activity alterations and vascular endothelial abnormalities, white matter changes, and disruption of the blood brain barrier, similar to those reported after ischemic/oxidative injury. Additionally, after repeated hypoxia/reoxygenation exposure, homozygous Townes had enhanced microglia activation. Our findings indicate that oxidative stress and stress-induced tissue damage is increased in susceptible brain regions, which may, in turn, contribute to neurocognitive deficits in SCD mice.

SUBMITTER: Khaibullina A

PROVIDER: S-EPMC7686096 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Sickle cell disease mice have cerebral oxidative stress and vascular and white matter abnormalities.

Khaibullina Alfia A Almeida Luis E F LEF Kamimura Sayuri S Zerfas Patricia M PM Smith Meghann L ML Vogel Sebastian S Wakim Paul P Vasconcelos Olavo M OM Quezado Martha M MM Horkayne-Szakaly Iren I Quezado Zenaide M N ZMN

Blood cells, molecules & diseases 20200904

Strokes are feared complications of sickle cell disease (SCD) and yield significant neurologic and neurocognitive deficits. However, even without detectable strokes, SCD patients have significant neurocognitive deficits in domains of learning and memory, processing speed and executive function. In these cases, mechanisms unrelated to major cerebrovascular abnormalities likely underlie these deficits. While oxidative stress and stress-related signaling pathways play a role in SCD pathophysiology, ...[more]

PMID: 32927249

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Project description:Krabbe Disease (KD) is an autosomal recessive disorder that results from loss-of-function mutations in the GALC gene, which encodes lysosomal enzyme galactosylceramidase (GALC). Functional deficiency of GALC is toxic to myelin-producing cells, which leads to progressive demyelination in both the central and peripheral nervous systems. It is hypothesized that accumulation of psychosine, which can only be degraded by GALC, is a primary initiator of pathologic cascades. Despite the central role of GALC in KD pathomechanism, investigations of GALC deficiency at a protein level are largely absent, due in part, to the lack of sensitive antibodies in the field. Leveraging two custom antibodies that can detect GALC at endogenous levels, we demonstrated that GALC protein is predominantly localized to oligodendrocytes in cerebral white matter of an infant brain, consistent with its functional role in myelination. Mature GALC could also be quantitatively detected as a 26 kDa band by western blotting and correlated to enzyme activity in brain tissues. The p.Ile562Thr polymorphic variant, which is over-represented in the KD population, was associated with reduced mature GALC protein and activity. In three infantile KD cases, homozygous null mutations in GALC lead to deficiency in total GALC protein and activity. Interestingly, although GALC activity was absent, normal levels of total GALC protein were detected by a sandwich ELISA using our custom antibodies in a later-onset KD brain, which suggests that the assay has the potential to differentiate infantile- and later-onset KD cases. Among the infantile KD cases, we quantified a 5-fold increase in psychosine levels, and observed increased levels of acid ceramidase, a key enzyme for psychosine production, and hyperglycosylated lysosomal-associated membrane protein 1, a marker for lysosomal activation, in periventricular white matter, a major pathological brain region, when compared with age-matched normal controls. While near complete demyelination was observed in these cases, we quantified that an early-infantile case (age of death at 10 months) had about 3-fold increases in both globoid cells, a pathological hallmark for KD, and CD8-positive T lymphocytes, a pathological marker for multiple sclerosis, in the white matter when compared with a slower progressing infantile case (age of death at 21 months), which suggests a positive correlation between clinical severity and neuropathology. Taken together, our findings have advanced the understanding of GALC protein biology in the context of normal and KD brain white matter. We also revealed new neuropathological changes that may provide insights to understand KD pathogenesis.

Project description:BackgroundChronic hypoxia-ischemia is a putative mechanism underlying the development of white matter hyperintensities (WMH) and microstructural disruption in cerebral small vessel disease. WMH fall primarily within deep white matter (WM) watershed regions. We hypothesized that elevated oxygen extraction fraction (OEF), a signature of hypoxia-ischemia, would be detected in the watershed where WMH density is highest. We further hypothesized that OEF would be elevated in regions immediately surrounding WMH, at the leading edge of growth.MethodsIn this cross-sectional study conducted from 2016 to 2019 at an academic medical center in St Louis, MO, participants (age >50) with a range of cerebrovascular risk factors underwent brain magnetic resonance imaging using pseudocontinuous arterial spin labeling, asymmetric spin echo, fluid-attenuated inversion recovery and diffusion tensor imaging to measure cerebral blood flow (CBF), OEF, WMH, and WM integrity, respectively. We defined the physiologic watershed as a region where CBF was below the 10th percentile of mean WM CBF in a young healthy cohort. We conducted linear regression to evaluate the relationship between CBF and OEF with structural and microstructural WM injury defined by fluid-attenuated inversion recovery WMH and diffusion tensor imaging, respectively. We conducted ANOVA to determine if OEF was increased in proximity to WMH lesions.ResultsIn a cohort of 42 participants (age 50-80), the physiologic watershed region spatially overlapped with regions of highest WMH lesion density. As CBF decreased and OEF increased, WMH density increased. Elevated watershed OEF was associated with greater WMH burden and microstructural disruption, after adjusting for vascular risk factors. In contrast, WM and watershed CBF were not associated with WMH burden or microstructural disruption. Moreover, OEF progressively increased while CBF decreased, in concentric contours approaching WMH lesions.ConclusionsChronic hypoxia-ischemia in the watershed region may contribute to cerebral small vessel disease pathogenesis and development of WMH. Watershed OEF may hold promise as an imaging biomarker to identify individuals at risk for cerebral small vessel disease progression.

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Sickle cell disease mice have cerebral oxidative stress and vascular and white matter abnormalities.

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Sickle cell disease mice have cerebral oxidative stress and vascular and white matter abnormalities.

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