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Ultrastructural analysis of blood-brain barrier breakdown in the peri-infarct zone in young adult and aged mice.

ABSTRACT: Following ischemia, the blood-brain barrier is compromised in the peri-infarct zone leading to secondary injury and dysfunction that can limit recovery. Currently, it is uncertain what structural changes could account for blood-brain barrier permeability, particularly with aging. Here we examined the ultrastructure of early and delayed changes (3 versus 72 h) to the blood-brain barrier in young adult and aged mice (3-4 versus 18 months) subjected to photothrombotic stroke. At both time points and ages, permeability was associated with a striking increase in endothelial caveolae and vacuoles. Tight junctions were generally intact although small spaces were detected in a few cases. In young mice, ischemia led to a significant increase in pericyte process area and vessel coverage whereas these changes were attenuated with aging. Stroke led to an expansion of the basement membrane region that peaked at 3 h and partially recovered by 72 h in both age groups. Astrocyte endfeet and their mitochondria were severely swollen at both times points and ages. Our results suggest that blood-brain barrier permeability in young and aged animals is mediated by transcellular pathways (caveolae/vacuoles), rather than tight junction loss. Further, our data indicate that the effects of ischemia on pericytes and basement membrane are affected by aging.

SUBMITTER: Nahirney PC

PROVIDER: S-EPMC4759675 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Ultrastructural analysis of blood-brain barrier breakdown in the peri-infarct zone in young adult and aged mice.

Nahirney Patrick C PC Reeson Patrick P Brown Craig E CE

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20151002 2

Following ischemia, the blood-brain barrier is compromised in the peri-infarct zone leading to secondary injury and dysfunction that can limit recovery. Currently, it is uncertain what structural changes could account for blood-brain barrier permeability, particularly with aging. Here we examined the ultrastructure of early and delayed changes (3 versus 72 h) to the blood-brain barrier in young adult and aged mice (3-4 versus 18 months) subjected to photothrombotic stroke. At both time points an ...[more]

PMID: 26661190

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Project description:Prior to assessing the impact of repeated HPβCD administration on the peri-infarct region of the brain, we first compared the transcriptome of the peri-infarct region to the equivalent region of the contralateral hemisphere in aged (18-month-old) mice at 7 weeks after distal middle cerebral artery occlusion + hypoxia (DH) stroke. The peri-infarct region was characterized by 3,910 differentially expressed genes. Of these, 2,123 were upregulated, many of which were also upregulated in infarcts at 7 weeks after stroke. For instance, the infarct and peri-infarct regions were both defined by the upregulation of degradative enzymes, TLRs, and scavenger receptors. In addition, the upregulation of Lpl, Lrp2, Ch25h, Apoe, Trem2, and Abca1 signified a divergence from lipid homeostasis. These alterations in innate immunity coincided with corresponding perturbations in adaptive immunity. The upregulation of Cd3d, Cd3e, Cd3g, Blnk, Sdc1 and Jchain suggests that chronic inflammation persists in peri-infarct regions for at least 7 weeks after stroke. Conversely, the DE analysis revealed that 1,787 genes were downregulated in peri-infarct regions compared to equivalent regions of the contralateral hemisphere. These genes were primarily involved in mitochondrial respiration and neuronal function. Together, these results demonstrate that the transcriptome of the peri-infarct region is characterized by the upregulation of genes involved in inflammation and lipid metabolism and the downregulation of genes involved in mitochondrial respiration and neuronal function. To evaluate the impact of HPβCD treatment on the transcriptome of the peri-infarct region, we also performed bulk RNA-Seq on brain tissue collected 7 weeks after DH stroke. For this analysis, we compared the peri-infarct regions of vehicle- and HPβCD-treated aged mice. The peri-infarct region of HPβCD-treated mice was characterized by 5,385 differentially expressed genes. The DE analysis revealed that peri-infarct regions of HPβCD-treated mice were characterized by the downregulation of multiple degradative enzymes, chemokine receptors, and scavenger receptors. In addition, the transcriptomic analysis demonstrated a restoration of lipid homeostasis in peri-infarct regions of HPβCD-treated mice compared to vehicle-injected mice, as evidenced by the downregulation of Lipa, Apoe, Lamp1, Npc1, and Npc2 and upregulation of Nceh1 and Ldlr. Reductions in innate and adaptive immune responses characterized peri-infarct regions of HPβCD-treated mice; these alterations are consistent with the attenuated chronic inflammation that characterized infarcts of the HPβCD-treated aged mice. These results demonstrate that HPβCD treatment after stroke attenuates chronic inflammation and promotes lipid metabolism in peri-infarct regions of aged mice. Additionally, the DE analysis revealed an upregulation of genes involved in myelin sheath structural integrity, such as Ina, Omg, and Nefl, and synaptic plasticity and neuroplasticity, such as Syn1, Bdnf, Nrg1, Negr1, and Nsg1. These results suggest that HPβCD treatment improves the structure and function of neurons in peri-infarct regions of aged mice after stroke.

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Dataset Information

Ultrastructural analysis of blood-brain barrier breakdown in the peri-infarct zone in young adult and aged mice.

Publications

Ultrastructural analysis of blood-brain barrier breakdown in the peri-infarct zone in young adult and aged mice.

Similar Datasets

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