Synthesis of human amyloid restricted to liver results in an Alzheimer disease–like neurodegenerative phenotype

Several lines of study suggest that peripheral metabolism of amyloid beta (Aß) is associated with risk for Alzheimer disease (AD). In blood, greater than 90% of Aß is complexed as an apolipoprotein, raising the possibility of a lipoprotein-mediated axis for AD risk. In this study, we report that genetic modification of C57BL/6J mice engineered to synthesise human Aß only in liver (hepatocyte-specific human amyloid (HSHA) strain) has marked neurodegeneration concomitant with capillary dysfunction, parenchymal extravasation of lipoprotein-Aß, and neurovascular inflammation. Moreover, the HSHA mice showed impaired performance in the passive avoidance test, suggesting impairment in hippocampal-dependent learning. Transmission electron microscopy shows marked neurovascular disruption in HSHA mice. This study provides causal evidence of a lipoprotein-Aß /capillary axis for onset and progression of a neurodegenerative process.

Blood Biomarkers of Parenchymal Damage in Ischemic Stroke Patients Treated With Revascularization Therapies

Purpose: Postischemic reperfusion injury may exacerbate cerebral damage and capillary dysfunction, leading to brain edema (BE), hemorrhagic transformation (HT), necrosis, and injury from free radicals with subsequent infarct growth (IG). Several plasmatic biomarkers involved in the ischemic cascade have been studied in relation to radiological and clinical outcomes of reperfusion injury in ischemic stroke with heterogeneous results. This article provides a brief overview of the contribution of circulating biomarkers to the pathophysiology of parenchymal damage in ischemic stroke patients treated with revascularization therapies. Methods: We included full reports with measurements of plasma markers in patients with acute ischemic stroke treated with revascularization therapies. Findings: Our research included a large number of observational studies investigating a possible role of circulating biomarkers in the development of parenchymal damage after acute stroke treatments. To make the results clearer, we divided the review in 4 sections, exploring the relation of different biomarkers with each of the indicators of parenchymal damage (HT, BE, IG, recanalization). Discussion and conclusion: Definite conclusions are difficult to draw because of heterogeneity across studies. However, our review seems to confirm an association between some circulating biomarkers (particularly matrix metalloproteinase-9) and occurrence of parenchymal damage in ischemic stroke patients treated with revascularization therapies.

Cerebral microcirculatory failure after subarachnoid hemorrhage is reversed by hyaluronidase

Aneurysmal subarachnoid hemorrhage remains one of the more devastating forms of stroke due in large part to delayed cerebral ischemia that appears days to weeks following the initial hemorrhage. Therapies exclusively targeting large caliber arterial vasospasm have fallen short, and thus we asked whether capillary dysfunction contributes to delayed cerebral ischemia after subarachnoid hemorrhage. Using a mouse model of subarachnoid hemorrhage and two-photon microscopy we showed capillary dysfunction unrelated to upstream arterial constriction. Subarachnoid hemorrhage decreased RBC velocity by 30%, decreased capillary pulsatility by 50%, and increased length of non-perfusing capillaries by 15%. This was accompanied by severe brain hypoxia and neuronal loss. Hyaluronidase, an enzyme that alters capillary blood flow by removing the luminal glycocalyx, returned RBC velocity and pulsatility to normal. Hyaluronidase also reversed brain hypoxia and prevented neuron loss typically seen after subarachnoid hemorrhage. Thus, subarachnoid hemorrhage causes specific changes in capillary RBC flow independent of arterial spasm, and hyaluronidase treatment that normalizes capillary blood flow can prevent brain hypoxia and injury after subarachnoid hemorrhage. Prevention or treatment of capillary dysfunction after subarachnoid hemorrhage may reduce the incidence or severity of subarachnoid hemorrhage-induced delayed cerebral ischemia.