Limor Raz1, Kiran Bhaskar2, John Weaver3, Sandro Marini4, Quanguang Zhang5, Jeffery F Thompson6, Candice Espinoza7, Sulaiman Iqbal8, Nicole M Maphis9, Lea Weston10, Laurel O Sillerud11, Arvind Caprihan12, John C Pesko13, Erik B Erhardt14, Gary A Rosenberg15. 1. Department of Neurology, 1 University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States. Electronic address: dr.liraz@gmail.com. 2. Department of Neurology, 1 University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States; Department of Molecular Genetics and Microbiology, 1 University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States. Electronic address: KBhaskar@salud.unm.edu. 3. BRaIN Imaging Center, 1 University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States. Electronic address: JMWeaver@salud.unm.edu. 4. Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, United States. Electronic address: smarini1@mgh.harvard.edu. 5. Department of Neuroscience and Regenerative Medicine, Department of Neurology, Augusta University, 1120 15th Street, Augusta, GA 30912, United States. Electronic address: qzhang@augusta.edu. 6. Department of Neurology, 1 University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States. Electronic address: JefThompson@salud.unm.edu. 7. Department of Neurology, 1 University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States. Electronic address: CEspinoza@salud.unm.edu. 8. Department of Neurology, 1 University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States. Electronic address: SIqbal@salud.unm.edu. 9. Department of Molecular Genetics and Microbiology, 1 University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States. Electronic address: NMaphis@salud.unm.edu. 10. Department of Molecular Genetics and Microbiology, 1 University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States. Electronic address: llweston@salud.unm.edu. 11. Department of Neurology, 1 University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States; MIND Research Network, 1 University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States. Electronic address: LSillerud@salud.unm.edu. 12. MIND Research Network, 1 University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States. Electronic address: acaprihan@mrn.org. 13. Department of Mathematics and Statistics, 1 University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States. 14. Department of Mathematics and Statistics, 1 University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States. Electronic address: erike@stat.unm.edu. 15. Department of Neurology, 1 University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States. Electronic address: GRosenberg@salud.unm.edu.
Abstract
BACKGROUND: Hypertension-induced microvascular brain injury is a major vascular contributor to cognitive impairment and dementia. We hypothesized that chronic hypoxia promotes the hyperphosphorylation of tau and cell death in an accelerated spontaneously hypertensive stroke prone rat model of vascular cognitive impairment. METHODS: Hypertensive male rats (n = 13) were fed a high salt, low protein Japanese permissive diet and were compared to Wistar Kyoto control rats (n = 5). RESULTS: Using electron paramagnetic resonance oximetry to measure in vivo tissue oxygen levels and magnetic resonance imaging to assess structural brain damage, we found compromised gray (dorsolateral cortex: p = .018) and white matter (corpus callosum: p = .016; external capsule: p = .049) structural integrity, reduced cerebral blood flow (dorsolateral cortex: p = .005; hippocampus: p < .001; corpus callosum: p = .001; external capsule: p < .001) and a significant drop in cortical oxygen levels (p < .05). Consistently, we found reduced oxygen carrying neuronal neuroglobin (p = .008), suggestive of chronic cerebral hypoperfusion in high salt-fed rats. We also observed a corresponding increase in free radicals (NADPH oxidase: p = .013), p-Tau (pThr231) in dorsolateral cortex (p = .011) and hippocampus (p = .003), active interleukin-1β (p < .001) and neurodegeneration (dorsolateral cortex: p = .043, hippocampus: p = .044). Human patients with subcortical ischemic vascular disease, a type of vascular dementia (n = 38; mean age = 68; male/female ratio = 23/15) showed reduced hippocampal volumes and cortical shrinking (p < .05) consistent with the neuronal cell death observed in our hypertensive rat model as compared to healthy controls (n = 47; mean age = 63; male/female ratio = 18/29). CONCLUSIONS: Our data support an association between hypertension-induced vascular dysfunction and the sporadic occurrence of phosphorylated tau and cell death in the rat model, correlating with patient brain atrophy, which is relevant to vascular disease.
BACKGROUND:Hypertension-induced microvascular brain injury is a major vascular contributor to cognitive impairment and dementia. We hypothesized that chronic hypoxia promotes the hyperphosphorylation of tau and cell death in an accelerated spontaneously hypertensive stroke prone rat model of vascular cognitive impairment. METHODS:Hypertensive male rats (n = 13) were fed a high salt, low protein Japanese permissive diet and were compared to Wistar Kyoto control rats (n = 5). RESULTS: Using electron paramagnetic resonance oximetry to measure in vivo tissue oxygen levels and magnetic resonance imaging to assess structural brain damage, we found compromised gray (dorsolateral cortex: p = .018) and white matter (corpus callosum: p = .016; external capsule: p = .049) structural integrity, reduced cerebral blood flow (dorsolateral cortex: p = .005; hippocampus: p < .001; corpus callosum: p = .001; external capsule: p < .001) and a significant drop in cortical oxygen levels (p < .05). Consistently, we found reduced oxygen carrying neuronal neuroglobin (p = .008), suggestive of chronic cerebral hypoperfusion in high salt-fed rats. We also observed a corresponding increase in free radicals (NADPH oxidase: p = .013), p-Tau (pThr231) in dorsolateral cortex (p = .011) and hippocampus (p = .003), active interleukin-1β (p < .001) and neurodegeneration (dorsolateral cortex: p = .043, hippocampus: p = .044). Humanpatients with subcortical ischemic vascular disease, a type of vascular dementia (n = 38; mean age = 68; male/female ratio = 23/15) showed reduced hippocampal volumes and cortical shrinking (p < .05) consistent with the neuronal cell death observed in our hypertensiverat model as compared to healthy controls (n = 47; mean age = 63; male/female ratio = 18/29). CONCLUSIONS: Our data support an association between hypertension-induced vascular dysfunction and the sporadic occurrence of phosphorylated tau and cell death in the rat model, correlating with patientbrain atrophy, which is relevant to vascular disease.
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