Hypoxia promotes tau hyperphosphorylation with associated neuropathology in vascular dysfunction
Open accessAbstract
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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Preclinical studies have reported an Aβ-independent relationship between cerebrovascular dysfunction and tau.
“Several preclinical studies also reported such Aβ‐independent relationship between cerebrovascular dysfunction and tau. 40 , 41”
From White matter hyperintensity modulates the amyloid‐tau‐cognition association and anti‐amyloid treatment efficacy in asymptomatic older adults (2025) · cites this paper as [41]
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“inflammation [54], and hypoxia-induced inflammation has been shown to promote GM damage and neurological deficits [13, 55-57].”
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Weaver, J. M. R., Jalal, F. Y., Yang, Y. R., Thompson, J., Rosenberg, G. A., & Liu, K. J. (2014) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2014.35 · Cited by 38 · cited 3× · see citing works
“surgically implanted for the detection of in vivo cortical O2 levels in WKY (n=5) and SHRSP/JPD (n=8), as previously described [28].”
Self-citationBinswanger’s disease: toward a diagnosis agreement and therapeutic approach
Huisa, B. N., & Rosenberg, G. A. (2014) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2014.956726 · Cited by 37 · cited 1× · see citing works
“the human brain as seen in the SHRSP [35].”
Self-citationNeuroinflammatory Markers in Spontaneously Hypertensive Rat Brain: An Immunohistochemical Study
Tayebati, S. K., Tomassoni, D., & Amenta, F. (2016) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527315666160527155014 · Cited by 33 · cited 12× · see citing works
“However, it is important to note that since ischemia is not a typical comorbidity associated with VCID, it is therefore important to assess the effects of JPD alone in SHRSP without a unilateral carotid artery occlusion.”
InfluentialShen, J., Sood, R., Weaver, J. M. R., Timmins, G. S., Schnell, A., Miyake, M., Kao, J. P. Y., Rosen, G. M., & Liu, K. J. (2009) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2009.89 · Cited by 30 · cited 3× · see citing works
“accurate signal-noise ratios and the peak-to-peak spectral linewidth was converted to pO2 values using a calibration curve, as was previously documented by our collaborators [30-32].”
MethodSelf-citationThe Cerebral Cortex of Spontaneously Hypertensive Rats: A Quantitative Microanatomical Study
Mignini, F., Vitaioli, L., Sabbatini, M., Tomassoni, D., & Amenta, F. (2004) · Clinical and Experimental Hypertension · doi:10.1081/ceh-120034135 · Cited by 29 · see citing works
Ritz, M., Grond‐Ginsbach, C., Engelter, S. T., & Lyrer, P. A. (2012) · Current Neurovascular Research · doi:10.2174/156720212799297074 · Cited by 25 · cited 1× · see citing works
“Evidence from other chronic hypoperfusion studies supports our claims, showing corresponding ROS [41] and RNS elevation [42] and lipid peroxidation [43], possibly suggestive of altered mitochondrial oxidative stress pathways in hypertensive rats, which may cause increased sensitivity to hypoxic insult [44].”
Ord, E., Shirley, R. B., McClure, J., McCabe, C., Kremer, E. J., Macrae, I. M., & Work, L. M. (2013) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2013.70 · Cited by 24 · cited 1× · see citing works
“spite of controversial evidence surrounding Ngb expression in neurological disease [45, 46], we”
Huang, Y., Wu, L., Xu, C., Yang, B., & Wang, R. (2006) · Cell Biochemistry and Biophysics · doi:10.1385/cbb:46:1:35 · Cited by 21 · cited 1× · see citing works
“In fact, Hgb and its degradation products have been recognized as neurotoxins [62], interfering with the NADPH system and promoting lipid peroxidation [63] in an animal model of VCID.”
Mencl, S., Garz, C., Niklass, S., Braun, H., Göb, E., Homola, G. A., Heinze, H., Reymann, K. G., Kleinschnitz, C., & Schreiber, S. (2013) · Experimental & Translational Stroke Medicine · doi:10.1186/2040-7378-5-8 · Cited by 20 · cited 1× · see citing works
“Another possible explanation is a state of capillary and arteriolar erythrocyte accumulation (stases), correlating with small vessel microbleeds observed on MRI [10, 61].”
Villarreal, A. E., Barron, R., Rao, K. S. J., & Britton, G. B. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-140144 · Cited by 14 · see citing works
Rat model of focal cerebral ischemia in the dominant hemisphere.
Zhang, H., Shen, Y. H., Wang, W., & Gao, H. (2015) · Europe PMC (PubMed Central) · Cited by 12 · see citing works
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Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease
Korte, N., Nortley, R., & Attwell, D. (2020) · Acta Neuropathologica · doi:10.1007/s00401-020-02215-w · Cited by 343 · see citing works
Hypoxia and brain aging: Neurodegeneration or neuroprotection?
Burtscher, J., Mallet, R. T., Burtscher, M., & Millet, G. P. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101343 · Cited by 346 · see citing works
“In rats (Raz et al., 2019), and in wild-type (Yagishita et al.”
BackgroundDietary salt promotes cognitive impairment through tau phosphorylation
Faraco, G., Hochrainer, K., Segarra, S. G., Schaeffer, S., Santisteban, M. M., Menon, A., Jiang, H., Holtzman, D. M., Anrather, J., & Iadecola, C. (2019) · Nature · doi:10.1038/s41586-019-1688-z · Cited by 236 · see citing works
White matter hyperintensity topography in Alzheimer's disease and links to cognition
Garnier‐Crussard, A., Bougacha, S., Wirth, M., Dautricourt, S., Sherif, S., Landeau, B., Gonneaud, J., De Flores, R., de la Sayette, V., Vivien, D., et al. (2022) · Alzheimer's & Dementia · doi:10.1002/alz.12410 · Cited by 170 · see citing works
Amyloid-beta and tau protein beyond Alzheimer’s disease
Abyadeh, M., Gupta, V., Paulo, J. A., Mahmoudabad, A. G., Shadfar, S., Mirshahvaladi, S., Gupta, V. B., Nguyen, C. T. O., Finkelstein, D. I., You, Y., et al. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.386406 · Cited by 121 · see citing works
“In turn, hypoperfusion may increase p-tau through the down-regulation of neuroglobin, a scavenger of ROS, increased free radicals, and the induction of neuroinflammatory cascade, ultimately leading to blood-brain barrier compromised permeability and neuronal cell death (Raz et al., 2019).”
BackgroundCerebrovascular disease promotes tau pathology in Alzheimer’s disease
Laing, K. K., Simoes, S., Baena-Caldas, G. P., Lao, P. J., Kothiya, M., Igwe, K. C., Chesebro, A. G., Houck, A. L., Pedraza, L., Hernandez, A. I., et al. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa132 · Cited by 93 · see citing works
Patel, V., & Edison, P. (2024) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp-2023-332661 · Cited by 80 · see citing works
Alzheimer-Related Cerebrovascular Disease in Down Syndrome
Lao, P., Gutierrez, J., Keator, D., Rizvi, B., Banerjee, A., Igwe, K., Laing, K. K., Sathishkumar, M. T., Moni, F., Andrews, H., et al. (2020) · Annals of Neurology · doi:10.1002/ana.25905 · Cited by 65 · see citing works
“It is possible that chronic hypoperfusion in posterior regions, particularly in the watershed zones that comprise the parietal lobes, induces ischemic damage and promotes taumediated neurodegeneration.(51) Some have argued that the posterior distribution of WMH in AD is secondary to tau-related pathology in a Walleria…”
BackgroundAssociation of Peripheral Blood Cell Profile With Alzheimer's Disease: A Meta-Analysis
Huang, L., Zhang, C., Wang, Y., & Wang, J. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.888946 · Cited by 70 · see citing works
Association of small vessel disease with tau pathology
Kapasi, A., Yu, L., Petyuk, V., Arfanakis, K., Bennett, D. A., & Schneider, J. A. (2022) · Acta Neuropathologica · doi:10.1007/s00401-021-02397-x · Cited by 55 · see citing works
“We conceptualize that SVD may be associated with tau phosphorylation through several downstream biological processes, including but not limited to neuroinflammation and oxidative stress associated with blood–brain barrier (BBB) dysfunction, which could impact key pathways that regulate intrinsic neuronal/cellular acti…”
BackgroundBai, X. H., & Zhang, M. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.689625 · Cited by 54 · see citing works
Pathological changes in neurovascular units: Lessons from cases of vascular dementia
Li, C., Wang, Y., Yan, X., Guo, Z., & Yang, Y. (2021) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13572 · Cited by 51 · see citing works
Systemic determinants of brain health in ageing
Smith, E. E., Biessels, G. J., Gao, V., Gottesman, R. F., Liesz, A., Parikh, N. S., & Iadecola, C. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-01016-z · Cited by 54 · see citing works
“A study in rats suggested a link between cerebral hypoxia and tau hyperphosphorylation, leading to cognitive impairment 80 .”
Neuroinflammation as a mechanism linking hypertension with the increased risk of Alzheimer’s disease
Bajwa, E., & Klegeris, A. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.336869 · Cited by 46 · see citing works
“Raz et al. (2019) reported reduced cerebral blood flow, decreased cortical oxygen levels, and reduced oxygen carrying neuronal neuroglobin in the spontaneously hypertensive and stroke-prone rat fed a high-salt, low-protein Japanese permissive diet, which is suggestive of chronic cerebral…”
The neuritic plaque in Alzheimer's disease: perivascular degeneration of neuronal processes
Hansra, G. K., Popov, G., Banaczek, P. O., Vogiatzis, M., Jegathees, T., Goldsbury, C. S., & Cullen, K. M. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2019.06.009 · Cited by 47 · see citing works
Tau as a potential therapeutic target for ischemic stroke
Chen, X., & Jiang, H. (2019) · Aging · doi:10.18632/aging.102547 · Cited by 44 · see citing works
“In addition, tau hyperphosphorylation could be caused by hypoxiadependent mechanism in vascular dysfunction models, such as the ischemic model [114].”
BackgroundWu, S., Huang, R., Zhang, R., Xiao, C., Wang, L., Luo, M., Song, N., Zhang, J., Yang, F. Y., Liu, X., et al. (2023) · Molecules · doi:10.3390/molecules28062598 · Cited by 43 · see citing works
“Previous studies have reported that Gas can exert neuroprotective effects by reducing the expression of Aβ and Tau proteins [22,27].”
BackgroundResultOxidative stress and chronic cerebral hypoperfusion: An overview from preclinical rodent models
Kimura, S., Iwata, M., Takase, H., Lo, E. H., & Arai, K. (2024) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x241305899 · Cited by 44 · see citing works
“49 In an experiment in which UCCAO was performed in SHR/SP rats followed by a high-salt, low-protein diet, there was evidence of myelin break-down and BBB disruption associated with increases in MMP-3, MMP-9 and TNF-a.”
Plasma VEGFA and PGF impact longitudinal tau and cognition in preclinical Alzheimer’s disease
Yang, H., Yau, W. W., Carlyle, B. C., Trombetta, B. A., Zhang, C. M., Shirzadi, Z., Schultz, A. P., Pruzin, J. J., Fitzpatrick, C. D., Kirn, D. R., et al. (2024) · Brain · doi:10.1093/brain/awae034 · Cited by 42 · see citing works
Ling, L., Feng, J., Wu, G., Wei, Z. C., Wang, J., Zhang, B., Liu, R., Liu, F., Wang, X., & Li, H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232416140 · Cited by 38 · see citing works
“Since hyperphosphorylation of tau is related to cognitive dysfunction [49,50], we evaluated the phosphorylation status of tau, and consistent with previous studies [30,43], we found that chronic hypoxia caused tau hyperphosphorylation in both the hippocampus of rats and in cell cultures.”
BackgroundResultEffect of ferroptosis on chronic cerebral hypoperfusion in vascular dementia
Fu, P., Chen, Y., Wu, M., Bao, B., Yin, X., Chen, Z., & Zhang, M. (2023) · Experimental Neurology · doi:10.1016/j.expneurol.2023.114538 · Cited by 36 · see citing works
Tract-defined regional white matter hyperintensities and memory
Rizvi, B. M., Lao, P. J., Colón, J. M., Hale, C., Igwe, K. C., Narkhede, A., Budge, M., Manly, J. J., Schupf, N., & Brickman, A. M. (2019) · NeuroImage Clinical · doi:10.1016/j.nicl.2019.102143 · Cited by 35 · see citing works
Insight into the Effects of High‐Altitude Hypoxic Exposure on Learning and Memory
Zhang, Z.-A., Sun, Y., Yuan, Z., Wang, L., Dong, Q., Zhou, Y., Zheng, G., Aschner, M., Zou, Y., & Luo, W. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/4163188 · Cited by 35 · see citing works
“Advanced studies have found that the phosphorylation of tau (P-tau) in the hippocampus tends to increase during hypoxia [115] and that there is an interaction between P-tau and cholinergic receptors [116].”
BackgroundEdwards, N. C., Lao, P. J., Alshikho, M. J., Ericsson, O. M., Rizvi, B. M., Petersen, M. E., O’Bryant, S. E., Aguilar, L. F., Simoes, S., Mapstone, M. E., et al. (2024) · Brain Communications · doi:10.1093/braincomms/fcae331 · Cited by 33 · see citing works
“Reports of associations between cerebrovascular disease and Alzheimer’s disease biomarkers are mixed, with some showing codependency 20 and others not.”
BackgroundWicha, P., Das, S., & Mahakkanukrauh, P. (2021) · Anatomy & Cell Biology · doi:10.5115/acb.20.290 · Cited by 30 · see citing works
“Tau hyperphosphorylation was found following cerebral ischemic damage in rat brain and hypoxia-dependent in vascular dysfunction model [85-87].”
BackgroundDuquette, A., Pernègre, C., Carpentier, A. V., & Leclerc, N. M. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2020.607680 · Cited by 29 · see citing works
“Chronic hypoxia was shown to induce tau hyperphosphorylation in a rat model (151).”
BackgroundTarawneh, R. (2023) · Biomolecules · doi:10.3390/biom13050830 · Cited by 29 · see citing works
“Tau hyperphosphorylation is observed in hypertensive rats that do not display Aβ pathology [158] and can be triggered by unilateral carotid artery occlusion even when Aβ levels are not elevated [159].”
BackgroundMaggiore, A., Latina, V., D’Erme, M., Amadoro, G., & Coccurello, R. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102578 · Cited by 24 · see citing works
Collateral Damage: Neurological Correlates of Non-Fatal Overdose in the Era of Fentanyl-Xylazine
Todaro, D. R., Volkow, N. D., Langleben, D. D., Shi, Z., & Wiers, C. E. (2024) · Neuroscience Insights · doi:10.1177/26331055241247156 · Cited by 24 · see citing works
“34 Both preclinical and human studies have identified increased levels of hyperphosphorylated tau in response to hypoxic brain injury, 35 supporting the hypothesis for a post-OD tauopathy potentially leading to progressive neurodegeneration.”
Association of cardiovascular risk factors and blood biomarkers with cognition: The HABS‐HD study
Jiang, X., O’Bryant, S. E., Johnson, L. A., Rissman, R. A., Yaffe, K. S., & The Health and Aging Brain Study (HABS‐HD) Study Team (2023) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.12394 · Cited by 21 · see citing works
“Mexican American, n (%) 311 (42) 326 (60) 150 (64) < 0.”
Brickman, A. M., & Rizvi, B. M. (2023) · Alzheimer s & Dementia · doi:10.1002/alz.13371 · Cited by 21 · see citing works
Huang, P., Chen, X., Hu, X., Zhou, Q., Lin, L., Jiang, S., Fu, H. Q., Xiong, Y., Zeng, H., Fang, M., et al. (2020) · NeuroMolecular Medicine · doi:10.1007/s12017-020-08602-6 · Cited by 21 · see citing works
Berisha, D. E., Rizvi, B. M., Chappel-Farley, M. G., Tustison, N. J., Taylor, L., Dave, A., Sattari, N. S., Chen, I. Y., Lui, K. K., Janecek, J. C., et al. (2025) · Neurology · doi:10.1212/wnl.0000000000213639 · Cited by 20 · see citing works
Hypoperfusion is a potential inducer of immunosuppressive network in Alzheimer's disease
Salminen, A. (2020) · Neurochemistry International · doi:10.1016/j.neuint.2020.104919 · Cited by 20 · see citing works
Rizvi, B. M., Sathishkumar, M. T., Kim, S., Márquez, F., Granger, S. J., Larson, M. S., Miranda, B. A., Hollearn, M. K., McMillan, L. C., Nan, B., et al. (2022) · NeuroImage Clinical · doi:10.1016/j.nicl.2022.103308 · Cited by 18 · see citing works
Chen, H. C., Cao, J., Zhang, Y.-S., Ma, Y., Zhang, L., Su, X., Gao, L., & Jing, Y. (2024) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2024.109570 · Cited by 16 · see citing works
Ohara, T., Furuta, Y., Hirabayashi, N., Hata, J., Hirakawa, Y., Honda, T., Yoshida, D., Shibata, M., Kitazono, T., & Ninomiya, T. (2020) · Journal of Diabetes Investigation · doi:10.1111/jdi.13220 · Cited by 15 · see citing works
Hippocampal volume loss in individuals with a history of non‐fatal opioid overdose
Todaro, D. R., Li, X., Pereira-Rufino, L. D. S., Manza, P., Nasrallah, I. M., Das, S. R., Childress, A. R., Kranzler, H. R., Volkow, N. D., Langleben, D. D., et al. (2023) · Addiction Biology · doi:10.1111/adb.13336 · Cited by 15 · see citing works
Tau Protein Alterations Induced by Hypobaric Hypoxia Exposure
Pena, E., Martin-Salamanca, R. S., Alam, S. E., Flores, K., & Arriaza, K. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25020889 · Cited by 16 · see citing works
Newman, M., Nik, S. H. M., Sutherland, G. T., Hin, N., Kim, W. S., Halliday, G. M., Jayadev, S., Smith, C., Laird, A. S., Lucas, C. W., et al. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa119 · Cited by 15 · see citing works
High altitude is associated with pTau deposition, neuroinflammation, and myelin loss
Iacono, D., Murphy, E. K., Sherman, P. M., Chapapas, H., Cerqueira, B., Christensen, C. L., Perl, D. P., & Sladky, J. H. (2022) · Scientific Reports · doi:10.1038/s41598-022-10881-x · Cited by 13 · see citing works
White Matter Hyperintensity as a Vascular Contribution to the AT(N) Framework
Ng, K. P., shen, J., Chiew, H. J., Ng, A., Kandiah, N., Rosa‐Neto, P., & Gauthier, S. G. (2023) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2023.53 · Cited by 12 · see citing works
Du, Y. J., Jin, M., Liu, Q., Zhao, J., Song, A., Li, W., Chang, H., Ma, F., & Huang, G. (2021) · Current Alzheimer Research · doi:10.2174/1567205018666210218144856 · Cited by 12 · see citing works
Cai, J., Ruan, J., Shao, X., Ding, Y., Xie, K., Tang, C., Yan, Z., Luo, E., & Jing, D. (2021) · High Altitude Medicine & Biology · doi:10.1089/ham.2020.0218 · Cited by 11 · see citing works
“It has been well established that hypoxia can trigger and aggravate Tau phosphorylation in the brain, and thus leads to subsequent cognitive impairment (Zhang et al., 2014; Raz et al., 2019).”
BOLD amplitude correlates of preclinical Alzheimer’s disease
Hrybouski, S., Das, S. R., Xie, L., Brown, C., Flamporis, M., Lane, J., Nasrallah, I. M., Detre, J. A., Yushkevich, P. A., & Wolk, D. A. (2025) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2025.03.007 · Cited by 11 · see citing works
“…— potentially via abnormal vascular remodeling (Bennett et al., 2018; Klohs et al., 2014; Lourenço et al., 2017; Park et al., 2020) — while hypoperfusion itself may further promote the accumulation of A β and tau (Chan et al., 2018; Liang et al., 2015; Raz et al., 2019; Zhang et al., 2010).”
Nunes, M. A., Toricelli, M., Schöwe, N. M., Malerba, H. N., Dong, K. E., Farah, D., Angelis, K. D., Irigoyen, M. C., Gobeil, F., Viel, T. A., et al. (2020) · Pharmaceuticals · doi:10.3390/ph13100288 · Cited by 11 · see citing works
“The hypoperfusion could lead to hypoxia, which is associated with Tau protein hyperphosphorylation and increased neuronal death [22].”
BackgroundBiskaduros, A., Glodzik, L., Louis, L. A. S., Rusinek, H., Pirraglia, E., Osorio, R. S., Butler, T., Li, Y., Xi, K., Tanzi, E. B., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.13800 · Cited by 9 · see citing works
“15,16 It would follow that lowering BP should stop these changes.”
BackgroundXu, Y., Zhang, S., Sun, Q., Wang, X., Chai, Y.-N., Mishra, C. K., Chandra, S. R., & Ai, J. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.586591 · Cited by 10 · see citing works
The effect of aging on brain injury and recovery after stroke
Baltan, S., Shi, Y., Keep, R. F., & Chen, J. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.04.001 · Cited by 10 · see citing works
Edwards, N. C., Lao, P. J., Alshikho, M. J., Ericsson, O. M., Rizvi, B. M., Petersen, M. E., O’Bryant, S. E., Aguilar, L. F., Simoes, S., Mapstone, M. E., et al. (2023) · medRxiv · doi:10.1101/2023.11.28.23298693 · Cited by 10 · see citing works
Current updates on latest basic research of scientific relevance in hypertensive dementia
Mogi, M., Takami, Y., Ihara, M., Yamashita, T., Takeda, S., Shibata, S., Node, K., Kario, K., Prevention of Cognitive Impairment by Hypertension Management (PCIHM) Working Group of the Japanese Society of Hypertension, Mogi, M., et al. (2025) · Hypertension Research · doi:10.1038/s41440-025-02417-3 · Cited by 9 · see citing works
“Moreover, chronic hypoxia in hypertensive rat models exacerbates NVU dysfunction by inducing tau hyperphosphorylation, neuroin fl ammation, and neurode-generation, paralleling the structural brain damage and cerebral hypoperfusion seen in human vascular dementia patients [164].”
Therapeutic roles of plants for 15 hypothesised causal bases of Alzheimer’s disease
Tyler, S. E. B., & Tyler, L. D. K. (2022) · Natural Products and Bioprospecting · doi:10.1007/s13659-022-00354-z · Cited by 10 · see citing works
“Hypertension raises brain amyloid and tau deposition (Raz et al., 2019) and impairs cerebral blood vessels, leading to brain ischemic damage and impaired cognitive function (Iadecola et al., 2016).”
BackgroundSwinford, C. G., Risacher, S. L., Vosmeier, A., Deardorff, R. L., Chumin, E. J., Džemidžić, M., Wu, Y., Gao, S., McDonald, B. C., Yoder, K. K., et al. (2022) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2023.06.014 · Cited by 9 · see citing works
Hu, Z., Hu, K., Wang, R., Gu, Y., Ouyang, W., Zhou, J., & Wen, Y. (2021) · Neuroscience Letters · doi:10.1016/j.neulet.2021.135774 · Cited by 9 · see citing works
Ling, L., Guo, Q., Cheng, Y., Gui, Y., Li, W., Zhao, Y., Xu, Z., Luo, Y., Wu, G., Wang, J., et al. (2025) · Journal of Advanced Research · doi:10.1016/j.jare.2025.06.033 · Cited by 9 · see citing works
“Previous studies have demonstrated that both staurosporine (STP) and amyloid-b (A b ) can induce cellular senescence [29–31].”
Nodding syndrome research, lessons learned from the NSETHIO project
de Merxem, D. G., Fodjo, J. N. S., Menon, S., Hotterbeekx, A., & Colebunders, R. (2019) · Cambridge Prisms Global Mental Health · doi:10.1017/gmh.2019.24 · Cited by 8 · see citing works
“2016) as well as by seizure-associated phenomena, including hypoxia (Raz et al. 2018) and repeated head injuries (Santangelo et al.”
BackgroundClinical correlates of obstructive sleep apnoea in idiopathic normal pressure hydrocephalus
Regalbuto, S., Zangaglia, R., Valentino, F., Todisco, M., Pacchetti, C., Ramusino, M. C., Mazzacane, F., Picascia, M., Arceri, S., Malomo, G., et al. (2024) · European Journal of Neurology · doi:10.1111/ene.16448 · Cited by 6 · see citing works
cis P-tau Accumulation Triggers Neurodegeneration after Ischemic Stroke
Seddigh, N., Taabodi, D., Dadzadi, M., & Shahpasand, K. (2024) · ACS Omega · doi:10.1021/acsomega.3c07285 · Cited by 7 · see citing works
Wertman, E. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13144202 · Cited by 6 · see citing works
Ashraf, G. M. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.78252 · Cited by 6 · see citing works
Parental History of Dementia Is Associated with Increased Small Vessel Cerebrovascular Disease
Stamm, B. C., Lao, P. J., Rizvi, B. M., Colón, J. M., Igwe, K. C., Chesebro, A. G., Maas, B., Schupf, N., Mayeux, R. P., Manly, J. J., et al. (2019) · The Journals of Gerontology Series A · doi:10.1093/gerona/glz291 · Cited by 6 · see citing works
“In autosomal-dominant forms of AD, there is elevated WMH burden up to 20 years prior to expected symptom onset (6); there is shared genetic risk for late-onset AD and vascular disease (7); and animal models show experimentally that small vessel cerebrovascular disease can induce AD-like tau pathology (8).”
BackgroundCerebral blood flow is associated with plasma and PET biomarkers of tau pathology in middle age
Houck, A. L., Alshikho, M. J., Lao, P. J., Pyne, J. D., Turney, I. C., Mazen, J., Benavides, A., Hale, C., Herman, M., Berroa, J., et al. (2025) · Brain Communications · doi:10.1093/braincomms/fcaf249 · Cited by 4 · see citing works
“32 Chronic cerebral hypoperfu-sion may also decrease brain glucose metabolism, leading to downregulation of tau O-GlcNAcylation, resulting in hyperphosphorylation via tau disruption in microtubules.”
Nawaz, A. D., Haider, M. Z., & Akhtar, S. (2023) · Biomolecules and Biomedicine · doi:10.17305/bb.2023.9680 · Cited by 4 · see citing works
“Hypoxia has been shown to accelerate hyper-phosphorylation of tau protein, a key hallmark in the pathogenesis of Alzheimer’s dementia [48].”
BackgroundStructural MRI in Alzheimer’s Disease
Last, B. S., Rizvi, B. M., & Brickman, A. M. (2020) · Oxford University Press eBooks · doi:10.1093/oso/9780190634230.003.0010 · Cited by 3 · see citing works
Lin, Z., Hong, Y., Hu, Y., Xiao, Q., Peng, S., Wu, D., Guo, T., & Jiang, D. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.70990 · Cited by 2 · see citing works
“40,41 This relationship may be driven by neuroinflammation and oxidative stress associated with blood-brain barrier dysfunction, 42 as well as impaired glym-phatic clearance due to vascular morphological changes.”
Gao, W., Xie, W., Xie, W., Jiang, C., Kang, Z., & Liu, N. (2024) · Folia Neuropathologica · doi:10.5114/fn.2024.136017 · Cited by 2 · see citing works
“Brain tissue hypoxia could result in the hyperphosphorylation of Tau protein [15].”
BackgroundUnique Pathology in the Locus Coeruleus of Individuals with Down Syndrome
Saternos, H., Hamlett, E. D., Guzman, S. J., Head, E., Granholm, A., & Ledreux, A. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-240043 · Cited by 2 · see citing works
“134 138 The effect of hypoxia in these subjects along with other death-related mechanisms may account for some of the lack of group difference observed in our study; specifi-cally, the outliers in our tau or glial staining which increase the variance of the data, an issue further enhanced by the…”
Khalilpour, J., Zangbar, H. S., Alipour, M. R., Pakdel, F. Q., Zavari, Z., & Shahabi, P. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03763-4 · Cited by 2 · see citing works
Berisha, D. E., Rizvi, B. M., Chappel-Farley, M. G., Tustison, N. J., Taylor, L., Dave, A., Sattari, N. S., Chen, I. Y., Lui, K. K., Janecek, J. C., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.28.577469 · Cited by 2 · see citing works
“However, there is growing evidence that intermittent hypoxia, a defining feature of OSA, may contribute to cerebral small vessel disease (CSVD), which may in turn facilitate neurodegeneration, age-related cognitive decline, and ultimately increased Alzheimer’s disease (AD) risk 35–37 .”
Ahn, S.-J., Goya, B., Bertomo, C., Sciortino, R. K., Racchumi, G., García‐Bonilla, L., Anrather, J., Iadecola, C., & Faraco, G. (2025) · Cardiovascular Research · doi:10.1093/cvr/cvaf217 · Cited by 1 · see citing works
Chronic high-altitude hypoxia exacerbates cognitive impairment and Alzheimer’s disease pathology
Jian, J.-M., Li, X., Xie, J., Hu, J.-N., Liang, J., Zhu, L., Zhao, H.-D., Zeng, F., Jin, W., Fan, D., et al. (2026) · Journal of Alzheimer s Disease · doi:10.1177/13872877261431844 · Cited by 1 · see citing works
Neuropathological and Behavioral Effects of Mild Traumatic Brain Injury at High Altitude
Browne, C. A., Korotcov, A. V., Cramer, N., Gangolli, M., Xu, X., Jaiswal, S., Bosomtwi, A., Hatch, K., Olsen, C., Groen, K., et al. (2026) · Journal of Neurotrauma · doi:10.1177/08977151261438726 · Cited by 1 · see citing works
“25 HA-associated alterations in vascular network, pericyte, and endothelial cell function within the hippocampus may restrict oxygenation of tissue despite an apparent increase in CBF. Low tissue oxygenation caused by suboptimal vascularization and weak neurovascular coupling within the hippocampus relative to the cor…”
InfluentialJuárez‐Cedillo, T., & Drier-Jonas, S. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.81892 · Cited by 1 · see citing works
“[49] found that the vascular alterations caused by hypertension promoted tau phosphorylation, leading to cell death and brain atrophy.”
BackgroundHemodynamics in Alzheimer’s Disease and Vascular Cognitive Impairment and Dementia
Cambronero, F. E., & Jefferson, A. L. (2020) · Oxford University Press eBooks · doi:10.1093/oso/9780190634230.003.0014 · Cited by 1 · see citing works
A Review of Low-Frequency EPR Technology for the Measurement of Brain pO2 and Oxidative Stress
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Self-citationAnimal models for vascular cognitive impairment
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Self-citationSimhadri, P. K., Rashid, S., Karri, S., Bhat, B. A., Babu, P. P., & Mehta, G. (2024) · doi:10.22541/au.171038051.17630622/v1
Spontaneously Hypertensive Rats Present Exacerbated Focal Stroke Behavioral Outcomes
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“These results reinforce the need to use animal stroke models with comorbidities, such as SAH, to improve translational perspectives for preclinical investigations of the treatment and prevention of stroke in humans.”
ResultAniol, V. A., Лазарева, Н. А., Kvichansky, A. A., Tret'yakova, L. V., Mamedova, D. I., Nedogreeva, O. A., Gulyaeva, N. V., & Stepanichev, M. Y. (2026) · Neurochemical Journal · doi:10.1134/s1819712426700182
Xiao, L., Green, J. M., Mochizuki, M., & Nakahara, T. (2026) · Cells · doi:10.3390/cells15151368
“Hypoxic stress also promotes tau pathology by activating tau kinases while suppressing phosphatases such as protein phosphatase 2A (PP2A), thereby facilitating tau hyperphosphorylation and aggregation [81,82].”
Sleep apnea in REM sleep as an amplifier of vascular contributions to Alzheimer's disease
Berisha, D. E., Benca, R. M., & Mander, B. A. (2026) · Alzheimer s & Dementia · doi:10.1002/alz.71735
“62 Recent evidence suggests that hypoxemia during REM sleep may be associated with greater MTL structural vulnerability and impaired MTLfunction,andthatcerebrovascularpathologymightmediatethese relationships.”
Blood Pressure Variability and Alzheimer Disease Biomarkers
Lohman, T., Sible, I. J., Ma, Y., Pahlevan, N. M., & Nation, D. A. (2026) · Hypertension · doi:10.1161/hypertensionaha.126.26768
Progressive Neurodegeneration From Anoxic Injury Following Perioperative Cardiac Arrest
Pandey, H. K., Gudenkauf, K. J., & Swaminathan, V. (2026) · Cureus · doi:10.7759/cureus.115034
A vascular component to the selective vulnerability of the medial temporal lobe to tau pathology
Doyon, V., Janelle, F., Sean, M., Vanderweyen, D., Cote, S. R., Huck, J., Tétreault, P., Lepage, J., Gutierrez, J., Bocti, C., et al. (2026) · Brain Communications · doi:10.1093/braincomms/fcag301
“20-23 Moreover, in vivo human imaging studies show that the vascular architecture supplying blood to the MTL is an important determinant of cognitive health, 24,25 thus raising the possibility that arterial structure supplying the MTL may be an important component of its selective vulnerability.”
- Authors
- 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.
- Affiliations
- University of New Mexico Health Sciences Center (US)
- Harvard University (US)
- Augusta University (US)
- Mind Research Network (US)
- Corresponding author
- Raz, Limor
- ORCID
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2019-06
- Volume
- 126
- Pages
- 124-136
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC6347559
- OpenAlex
- W2884578044
- Cited by
- 84
- References
- 75
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 18 · 2023: 11 · 2022: 10 · 2021: 10 · 2020: 11 · 2019: 9
- FWCI
- 3.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- University of New Mexico Health Sciences Center Institutional Animal Care and Use Committee
- Topics
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- chronic hypoxia, tau hyperphosphorylation, hypertension, vascular cognitive impairment, subcortical ischemic vascular disease, cerebral hypoperfusion, neuroglobin, NADPH oxidase, IL-1β, neuronal cell death, brain atrophy, white matter injury, cerebral blood flow, vascular dementia
- MeSH terms
- Aged, Animals, Brain, Female, Humans, Hypertension, Male, Middle Aged, Phosphorylation, Rats, Inbred SHR, Rats, Inbred WKY, Dementia, Vascular, Cell Hypoxia, tau Proteins, Rats
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