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

doi:10.1016/j.nbd.2018.07.009

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 journal › Review article › peer-review

46 Scopus citations

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 language	English (US)
Pages (from-to)	124-136
Number of pages	13
Journal	Neurobiology of Disease
Volume	126
DOIs	https://doi.org/10.1016/j.nbd.2018.07.009
State	Published - Jun 2019
Externally published	Yes

Keywords

Hypertension
Hypoxia
Neurodegeneration
SHRSP
Tau

ASJC Scopus subject areas

Neurology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.nbd.2018.07.009

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Raz, L., Bhaskar, K., Weaver, J., Marini, S., Zhang, Q., Thompson, J. F., Espinoza, C., Iqbal, S., Maphis, N. M., Weston, L., Sillerud, L. O., Caprihan, A., Pesko, J. C., Erhardt, E. B., & Rosenberg, G. A. (2019). Hypoxia promotes tau hyperphosphorylation with associated neuropathology in vascular dysfunction. Neurobiology of Disease, 126, 124-136. https://doi.org/10.1016/j.nbd.2018.07.009

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

@article{7eab3701481944a39f9f7d6845401c54,

title = "Hypoxia promotes tau hyperphosphorylation with associated neuropathology in vascular dysfunction",

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.",

keywords = "Hypertension, Hypoxia, Neurodegeneration, SHRSP, Tau",

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.}",

note = "Funding Information: The animal protocol was approved by the University of New Mexico Health Sciences Center Institutional Animal Care and Use Committee (IACUC), adhering to the Humane Care and Use of Laboratory Animals Policy by NIH. Studies of the patients with cognitive impairment were approved by the University of New Mexico Human Research Committee (ARFprotocol #: 15-200248-HSC; grant # related to protocol: 2 RO1 NS045847-071A). All participants have consented to participate in the study. The authors would like to thank the students in the lab: Anna Diaz and Carolyn Nighbert for their technical help with experiments. We also thank Yirong Yang, PhD for acquiring the MRI of our rats and to Jim Liu, PhD for his expert guidance in the interpretation of the EPR oximetry and free radical data. Finally, we extend our gratitude to Fakhreya Jalal, PhD for establishing the high salt rat models in the lab, on which this research project is based. Funding Information: This study is supported by NIH/NINDS R01 NS045847-07A1 and R01 NS083704. Publisher Copyright: {\textcopyright} 2018",

year = "2019",

month = jun,

doi = "10.1016/j.nbd.2018.07.009",

language = "English (US)",

volume = "126",

pages = "124--136",

journal = "Neurobiology of Disease",

issn = "0969-9961",

publisher = "Academic Press Inc.",

}

TY - JOUR

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.

N1 - Funding Information: The animal protocol was approved by the University of New Mexico Health Sciences Center Institutional Animal Care and Use Committee (IACUC), adhering to the Humane Care and Use of Laboratory Animals Policy by NIH. Studies of the patients with cognitive impairment were approved by the University of New Mexico Human Research Committee (ARFprotocol #: 15-200248-HSC; grant # related to protocol: 2 RO1 NS045847-071A). All participants have consented to participate in the study. The authors would like to thank the students in the lab: Anna Diaz and Carolyn Nighbert for their technical help with experiments. We also thank Yirong Yang, PhD for acquiring the MRI of our rats and to Jim Liu, PhD for his expert guidance in the interpretation of the EPR oximetry and free radical data. Finally, we extend our gratitude to Fakhreya Jalal, PhD for establishing the high salt rat models in the lab, on which this research project is based. Funding Information: This study is supported by NIH/NINDS R01 NS045847-07A1 and R01 NS083704. Publisher Copyright: © 2018

PY - 2019/6

Y1 - 2019/6

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.

KW - Hypertension

KW - Hypoxia

KW - Neurodegeneration

KW - SHRSP

KW - Tau

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U2 - 10.1016/j.nbd.2018.07.009

DO - 10.1016/j.nbd.2018.07.009

M3 - Review article

C2 - 30010004

AN - SCOPUS:85050662950

SN - 0969-9961

VL - 126

SP - 124

EP - 136

JO - Neurobiology of Disease

JF - Neurobiology of Disease

ER -

Hypoxia promotes tau hyperphosphorylation with associated neuropathology in vascular dysfunction

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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