Role of Delayed Neuroglial Activation in Impaired Cerebral Blood Flow Restoration Following Comorbid Injury.

Besides other causes, ischemia and Alzheimer's disease pathology is also linked to decreased cerebral blood flow (CBF). There is little or no consensus about the role of neuroglial cells in maintaining CBF in various neuropathologies. This consensus becomes scarcer when it comes to clinical and experimental cases of comorbid Abeta-amyloid (Aß) toxicity and ischemia. Here, a comorbid rat model of Aß toxicity and endothelin-1 induced ischemia (ET1) not only demonstrated the appearance of axotomized phagocytosed pyknotic neurons (NeuN) immediately after the injury, but also showed a diversity of continuously changing neuroglia (MHC Class II/OX6, Iba1) and macrophage (Iba1/CD68) phenotypes with round, stout somas, and retracted processes. This is indicative of a response to a concomitant increase in large fluid-filled spaces due to the vascular leakage. Ironically 4 weeks after the injury despite a conclusive reduction in neurons, CBF restoration in ET1 rats was associated with a massive increase in neuroglial cell numbers, hypertrophy, ramification, and soma sizes bordering the continuously reducing lesion core and inflamed vasculature, possibly to shield their leaky phenotype. Astrocytes were also found to be releasing matrix metalloproteinase9 (MMP9), which stabilized matrix ligand ß-dystroglycan (ß-DG) in repaired or functional vessels. Changing neuroglia phenotypes, responses, motility, astrocytic recruitment of MMP9, and ß-DG stabilization implies the role of communication between neuroglia and endothelium in recovering CBF, in the absence of neurons, in ET1 rats compared to Aß+ET1 rats, which showed characteristics delayed neuroglial activation. Stimulation of timely neuroglial reactivity may serve as a viable strategy to compensate for the neuronal loss in restoring CBF in comorbid cases of ischemia and Aß toxicity.

Correction to: Role of Delayed Neuroglial Activation in Impaired Cerebral Blood Flow Restoration Following Comorbid Injury.

The original version of this article contained a random order of part labels for Fig. 4. The correct caption of Fig. 4 with correct order of part labels is given below.

Establishing the SouthWestern Academic Health Network (SWAHN): A Survey Exploring the Needs of Academic and Community Networks in SouthWestern Ontario.

With the evolving fields of health research, health professional education and advanced clinical care comes a need to bring researchers, educators and health care providers together to enhance communication, knowledge-sharing and interdisciplinary collaboration. There is also a need for active collaboration between academic institutions and community organizations to improve health care delivery and health outcomes in the community setting. In Canada, an Academic Health Sciences Network model has been proposed to achieve such activities. The SouthWestern Academic Health Network (SWAHN) has been established among three universities, three community colleges, community hospitals, community-based organizations and health care providers and two Local Health Integrated Networks (LHINs) in Southwestern Ontario. A survey was conducted to understand the characteristics, activities, existing partnerships, short- and long-term goals of the academic and community health networks in SouthWestern Ontario to inform the development of SWAHN moving forward. A total of 114 health networks were identified from the two participating LHINs, 103 community health networks and 11 academic health networks. A mailed survey was sent to all networks and responses were analyzed using both quantitative and qualitative approaches. The short- and long-term goals of these networks were categorized into five main themes: Public Health, Education, Research, System Delivery and Special Populations. Overall, this study helped to elicit important information from the academic and community based networks, which will inform the future work of SWAHN. This research has also demonstrated the significance of collecting information from both academic and community partners during the formation of other interdisciplinary health networks.

The spatial cerebral damage caused by larger infarct and ß-amyloid toxicity is driven by the anatomical/functional connectivity.

Large cerebral infarctions are major predictors of death and severe disability from stroke. Conversely, data concerning these types of infarctions and the affected adjacent brain circuits are scarce. It remains to be determined if the co-morbid concurrence of large infarct and ß-amyloid (Aß) toxicity can precipitate the early development of dementia. Here, we described a dose-dependent effect of a unilateral striatal injection of vasoconstrictive endothelin-1 (ET-1) along with Aß toxicity on CNS pathogenesis; driven by the anatomical and functional networks within a brain circuit. After 21 days of treatment, a high dose (60 pmol) of ET-1 (E60) alone caused the greatest increase in neuroinflammation, mainly in the ipsilateral striatum and distant regions with synaptic links to the striatal lesion such as white matter (subcortical white matter, corpus callosum, internal capsule, anterior commissure), gray matter (globus pallidus, thalamus), and cortices (cingulate, motor, somatosensory, entorhinal). The combined E60 + Aß treatment also extended perturbation in the contralateral hemisphere of these rats, such as increased deposition of amyloid precursor protein fragments associated with the appearance of degenerating cells and the leakage of laminin from the basement membrane across a compromised blood-brain barrier. However, the cerebral damage induced by the 6 pmol ET-1 (E6), Aß and E6 + Aß rats was not detrimental enough to injure the complete network. The appreciation of the causal interactions among distinct anatomical units in the brain after ischemia and Aß toxicity will help in the design of effective and alternative therapeutics that may disassociate the synergistic or additive association between the infarcts and Aß toxicity.

Spatial Dynamics of Vascular and Biochemical Injury in Rat Hippocampus Following Striatal Injury and Aß Toxicity.

The hippocampus, a brain region vital for memory and learning, is sensitive to the damage caused by ischemic/hypoxic stroke and is one of the main regions affected by Alzheimer's disease. The pathological changes that might occur in the hippocampus and its connections, because of cerebral injury in a distant brain region, such as the striatum, have not been examined. Therefore, in the present study, we evaluated the combined effects of endothelin-1-induced ischemia (ET1) in the striatum and ß-amyloid (Aß) toxicity on hippocampal pathogenesis, dictated by the anatomical and functional intra- and inter-regional hippocampal connections to the striatum. The hippocampal pathogenesis induced by Aß or ET1 alone was not severe enough to significantly affect the entire circuit of the hippocampal network. However, the combination of the two pathological states (ET1 + Aß) led to an exacerbated increase in neuroinflammation, deposition of the amyloid precursor protein (APP) fragments with the associated appearance of degenerating cells, and blood-brain-barrier disruption. This was observed mainly in the hippocampal formation (CA2 and CA3 regions), the dentate gyrus as well as distinct regions with synaptic links to the hippocampus such as entorhinal cortex, thalamus, and basal forebrain. In addition, ET1 + Aß-treated rats also demonstrated protracted loss of AQP4 depolarization, dissolution of ß-dystroglycan, and basement membrane laminin with associated IgG and dysferlin leakage. Spatial dynamics of hippocampal injury in ET1 + Aß rats may provide a valuable model to study new targets for clinical therapeutic applications, specifically when areas remotely connected to hippocampus are damaged.