Amyloid β aggregation induces human brain microvascular endothelial cell death with abnormal actin organization

Take, Yushiro; Chikai, Yusaku; Shimamori, Keiya; Kuragano, Masahiro; Kurita, Hiroki; Tokuraku, Kiyotaka

doi:10.1016/j.bbrep.2021.101189

Cited by 8 publications

(7 citation statements)

References 41 publications

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“…Cerebral EC apoptosis contributes to the pathogenesis of AD, sporadic and familial forms of CAA (Take et al., 2022 ); Wang, Zhang, et al., 2020 ), being one of the main culprits for the appearance of micro and macro‐hemorrhages (Wang et al., 2020 ). We have previously shown that the vasculotropic Dutch Aβ mutant, AβQ22, highly associated with CAA, promotes, TRAIL DRs (DR4/5)‐mediated cerebral EC apoptosis (through direct binding to these receptors), BBB permeability, and angiogenesis deficits similarly to Aβ40‐WT, albeit with faster kinetics (Fossati et al., 2010 , 2012b ; Parodi‐Rullan et al., 2020 , 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Homocysteine potentiates amyloid β‐induced death receptor 4‐ and 5‐mediated cerebral endothelial cell apoptosis, blood brain barrier dysfunction and angiogenic impairment

Carey,

Parodi‐Rullan,

Vazquez‐Torres

et al. 2024

Aging Cell

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Cerebrovascular dysfunction has been implicated as a major contributor to Alzheimer's Disease (AD) pathology, with cerebral endothelial cell (cEC) stress promoting ischemia, cerebral‐blood flow impairments and blood–brain barrier (BBB) permeability. Recent evidence suggests that cardiovascular (CV)/cerebrovascular risk factors, including hyperhomocysteinemia (Hhcy), exacerbate AD pathology and risk. Yet, the underlying molecular mechanisms for this interaction remain unclear. Our lab has demonstrated that amyloid beta 40 (Aβ40) species, and particularly Aβ40‐E22Q (AβQ22; vasculotropic Dutch mutant), promote death receptor 4 and 5 (DR4/DR5)‐mediated apoptosis in human cECs, barrier permeability, and angiogenic impairment. Previous studies show that Hhcy also induces EC dysfunction, but it remains unknown whether Aβ and homocysteine function through common molecular mechanisms. We tested the hypotheses that Hhcy exacerbates Aβ‐induced cEC DR4/5‐mediated apoptosis, barrier dysfunction, and angiogenesis defects. This study was the first to demonstrate that Hhcy specifically potentiates AβQ22‐mediated activation of the DR4/5‐mediated extrinsic apoptotic pathway in cECs, including DR4/5 expression, caspase 8/9/3 activation, cytochrome‐c release and DNA fragmentation. Additionally, we revealed that Hhcy intensifies the deregulation of the same cEC junction proteins mediated by Aβ, precipitating BBB permeability. Furthermore, Hhcy and AβQ22, impairing VEGF‐A/VEGFR2 signaling and VEGFR2 endosomal trafficking, additively decrease cEC angiogenic capabilities. Overall, these results show that the presence of the CV risk factor Hhcy exacerbates Aβ‐induced cEC apoptosis, barrier dysfunction, and angiogenic impairment. This study reveals specific mechanisms through which amyloidosis and Hhcy jointly operate to produce brain EC dysfunction and death, highlighting new potential molecular targets against vascular pathology in comorbid AD/CAA and Hhcy conditions.

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Section: Discussionmentioning

confidence: 99%

Homocysteine potentiates amyloid β‐induced death receptor 4‐ and 5‐mediated cerebral endothelial cell apoptosis, blood brain barrier dysfunction and angiogenic impairment

Carey,

Parodi‐Rullan,

Vazquez‐Torres

et al. 2024

Aging Cell

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“…The pig is of interest as translational model for neurological disorders, most of which are hitherto considered to have neurodevelopmental origins, and many of which manifest early with vascular problems (Ishihara et al, 2023; Ouellette and Lacoste, 2021). As an example, amyloid deposits in microvessels emerge before large plaques appear (Take et al, 2022). Extensive data on fetal and early postnatal development are sparse.…”

Section: Discussionmentioning

confidence: 99%

Vascular development of fetal and postnatal neocortex of the pig, the European wild boarSus scrofa

Sobierajski,

Czubay,

Beemelmans

et al. 2024

Preprint

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The development of the brains vascular system is a predominantly prenatal process in mammalian species and required for neurogenesis and further brain development. Our recent work on fetal pig has revealed that many neurodevelopmental processes start well before birth and proceed rapidly reaching near-mature status already around birth. Here, we analyzed the development of neocortical vasculature from embryonic day (E) 45 onwards (gestation in pig lasts 114 days) using qualitative and quantitative image analyses and protein blots. In all cortical layers, vessel volume from total brain volume at E100 resembled that of a postnatal day (P) 30 piglet. Endothelial cells expressed the tight junction protein claudin-5 from E45 onwards. GFAP+ and AQP4+ astrocytes, PDGFRβ+ pericytes and α-SMA+ smooth muscle cells are detectable near vessels at E60 suggesting an early assembly of blood-brain barrier components. The vascular system in the visual cortex is advanced before birth with an almost mature pattern at E100. Findings were confirmed by blots which showed a steady increase of expression of tight junction and angiogenesis-related proteins (claudin-5, occludin, VE-cadherin, PECAM-1/CD31) from E65 onwards until P90. The expression profile was similar in visual and somatosensory cortex. Together, we report a rapid maturation of the vascular system in pig cortex. Regarding activity-dependent aspects, the data suggest that angiogenesis might be influenced by spontaneous rather than sensory-evoked activity.

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“…Therefore, it has been suggested that galectin-7 can influence the expression of myosin and actin proteins in vascular intima and vascular smooth muscle by influencing signaling pathways involving signaling molecules such as kinase C (PKC), Rho kinase, G protein, and oxidative stress. Meanwhile, galectin-7 also influences inflammatory signaling pathways by interacting with myosin light chain 1/3, myosin-1, myosin, myoglobin, and troponin C proteins ( Smeda et al, 1999 ; Shimomura et al, 2004 ; Khan et al, 2006 ; Hayakawa et al, 2011 ; Ghiso et al, 2014 ; Zhou et al, 2018 ; Xue-Qin et al, 2020 ; Take et al, 2022 ). Taken together, the results of this study and numerous other studies indicate that the galectin-7 is involved in the regulation of activities of a relatively large number of related proteins in diverse pathways and proteins common to multiple signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Human Galectin-7 Gene LGALS7 Promoter Sequence Polymorphisms and Risk of Spontaneous Intracerebral Hemorrhage: A Prospective Study

Wang

Tian

Zhang

et al. 2022

Front. Mol. Neurosci.

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Background and purposeDespite evidence for the role of genetic factors in stroke, only a small proportion of strokes have been clearly attributed to monogenic factors, due to phenotypic heterogeneity. The goal of this study was to determine whether a significant relationship exists between human galectin-7 gene LGALS7 promoter region polymorphisms and the risk of stroke due to non-traumatic intracerebral hemorrhage (ICH).MethodsThis two-stage genetic association study included an initial exploratory stage followed by a discovery stage. During the exploratory stage, transgenic galectin-7 mice or transgenic mice with the scrambled sequence of the hairpin structure –silenced down gene LGALS7—were generated and then expressed differentially expressed proteins and galectin-7-interacting proteins were identified through proteomic analysis. During the discovery stage, a single-nucleotide polymorphism (SNP) genotyping approach was used to determine associations between 2 LGALS7 SNPs and ICH stroke risk for a cohort of 24 patients with stroke of the Chinese Han population and 70 controls.ResultsDuring the exploratory phase, LGALS7 expression was found to be decreased in TGLGALS–DOWN mice as compared to its expression in TGLGALS mice. During the discovery phase, analysis of LGALS7 sequences of 24 non-traumatic ICH cases and 70 controls led to the identification of 2 ICH susceptibility loci: a genomic region on 19q13.2 containing two LGALS7 SNPs, rs567785577 and rs138945880, whereby the A allele of rs567785577 and the T allele of rs138945880 were associated with greater risk of contracting ICH [for T and A vs. C and G, unadjusted odds ratio (OR) = 13.5; 95% CI = 2.249–146.5; p = 0.002]. This is the first study to genotype the galectin-7 promoter in patients with hemorrhagic stroke. Genotype and allele association tests and preliminary analysis of patients with stroke revealed that a single locus may be a genetic risk factor for hemorrhagic stroke.ConclusionA and T alleles of two novel SNP loci of 19q13.2, rs567785577 and rs138945880, respectively, were evaluated for associations with susceptibility to ICH. Further studies with expanded case numbers that include subjects of other ethnic populations are needed to elucidate mechanisms underlying associations between these SNPs and ICH risk.

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Amyloid β aggregation induces human brain microvascular endothelial cell death with abnormal actin organization

Cited by 8 publications

References 41 publications

Homocysteine potentiates amyloid β‐induced death receptor 4‐ and 5‐mediated cerebral endothelial cell apoptosis, blood brain barrier dysfunction and angiogenic impairment

Homocysteine potentiates amyloid β‐induced death receptor 4‐ and 5‐mediated cerebral endothelial cell apoptosis, blood brain barrier dysfunction and angiogenic impairment

Vascular development of fetal and postnatal neocortex of the pig, the European wild boarSus scrofa

Human Galectin-7 Gene LGALS7 Promoter Sequence Polymorphisms and Risk of Spontaneous Intracerebral Hemorrhage: A Prospective Study

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