Hypoxia promotes tau hyperphosphorylation with associated neuropathology in vascular dysfunction

Limor Raz, Kiran Bhaskar, John Weaver, Sandro Marini, Quanguang Zhang, Jeffery F. Thompson, Candice Espinoza, Sulaiman Iqbal, Nicole M. Maphis, Lea Weston, Laurel O. Sillerud, Arvind Caprihan, John C. Pesko, Erik B. Erhardt, Gary A. Rosenberg

Research output: Contribution to journalReview article

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)124-136
Number of pages13
JournalNeurobiology of Disease
Volume126
DOIs
StatePublished - Jun 1 2019

Fingerprint

Blood Vessels
Hippocampus
Cell Death
Corpus Callosum
Oxygen
Vascular Diseases
Cerebrovascular Circulation
Salts
Hypertension
Vascular Dementia
Oximetry
Inbred WKY Rats
NADPH Oxidase
Electron Spin Resonance Spectroscopy
Brain
Interleukin-1
Brain Injuries
Free Radicals
Atrophy
Dementia

Keywords

  • Hypertension
  • Hypoxia
  • Neurodegeneration
  • SHRSP
  • Tau

ASJC Scopus subject areas

  • Neurology

Cite this

Hypoxia promotes tau hyperphosphorylation with associated neuropathology in vascular dysfunction. / Raz, Limor; Bhaskar, Kiran; Weaver, John; Marini, Sandro; Zhang, Quanguang; Thompson, Jeffery F.; Espinoza, Candice; Iqbal, Sulaiman; Maphis, Nicole M.; Weston, Lea; Sillerud, Laurel O.; Caprihan, Arvind; Pesko, John C.; Erhardt, Erik B.; Rosenberg, Gary A.

In: Neurobiology of Disease, Vol. 126, 01.06.2019, p. 124-136.

Research output: Contribution to journalReview article

Raz, L, Bhaskar, K, Weaver, J, Marini, S, Zhang, Q, Thompson, JF, Espinoza, C, Iqbal, S, Maphis, NM, Weston, L, Sillerud, LO, Caprihan, A, Pesko, JC, Erhardt, EB & Rosenberg, GA 2019, 'Hypoxia promotes tau hyperphosphorylation with associated neuropathology in vascular dysfunction', Neurobiology of Disease, vol. 126, pp. 124-136. https://doi.org/10.1016/j.nbd.2018.07.009
Raz, Limor ; Bhaskar, Kiran ; Weaver, John ; Marini, Sandro ; Zhang, Quanguang ; Thompson, Jeffery F. ; Espinoza, Candice ; Iqbal, Sulaiman ; Maphis, Nicole M. ; Weston, Lea ; Sillerud, Laurel O. ; Caprihan, Arvind ; Pesko, John C. ; Erhardt, Erik B. ; Rosenberg, Gary A. / Hypoxia promotes tau hyperphosphorylation with associated neuropathology in vascular dysfunction. In: Neurobiology of Disease. 2019 ; Vol. 126. pp. 124-136.
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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.",
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author = "Limor Raz and Kiran Bhaskar and John Weaver and Sandro Marini and Quanguang Zhang and Thompson, {Jeffery F.} and Candice Espinoza and Sulaiman Iqbal and Maphis, {Nicole M.} and Lea Weston and Sillerud, {Laurel O.} and Arvind Caprihan and Pesko, {John C.} and Erhardt, {Erik B.} and Rosenberg, {Gary A.}",
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T1 - Hypoxia promotes tau hyperphosphorylation with associated neuropathology in vascular dysfunction

AU - Raz, Limor

AU - Bhaskar, Kiran

AU - Weaver, John

AU - Marini, Sandro

AU - Zhang, Quanguang

AU - Thompson, Jeffery F.

AU - Espinoza, Candice

AU - Iqbal, Sulaiman

AU - Maphis, Nicole M.

AU - Weston, Lea

AU - Sillerud, Laurel O.

AU - Caprihan, Arvind

AU - Pesko, John C.

AU - Erhardt, Erik B.

AU - Rosenberg, Gary A.

PY - 2019/6/1

Y1 - 2019/6/1

N2 - 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.

AB - 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.

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KW - Hypoxia

KW - Neurodegeneration

KW - SHRSP

KW - Tau

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