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Chronic Sustained Hypoxia Leads to Brainstem Tauopathy and Declines the Power of Rhythms in the Ventrolateral Medulla: Shedding Light on a Possible Mechanism

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Abstract

Hypoxia, especially the chronic type, leads to disruptive results in the brain that may contribute to the pathogenesis of some neurodegenerative diseases such as Alzheimer’s disease (AD). The ventrolateral medulla (VLM) contains clusters of interneurons, such as the pre-Bötzinger complex (preBötC), that generate the main respiratory rhythm drive. We hypothesized that exposing animals to chronic sustained hypoxia (CSH) might develop tauopathy in the brainstem, consequently changing the rhythmic manifestations of respiratory neurons. In this study, old (20–22 months) and young (2–3 months) male rats were subjected to CSH (10 ± 0.5% O2) for ten consecutive days. Western blotting and immunofluorescence (IF) staining were used to evaluate phosphorylated tau. Mitochondrial membrane potential (MMP or ∆ψm) and reactive oxygen species (ROS) production were measured to assess mitochondrial function. In vivo diaphragm’s electromyography (dEMG) and local field potential (LFP) recordings from preBötC were employed to assess the respiratory factors and rhythmic representation of preBötC, respectively. Findings showed that ROS production increased significantly in hypoxic groups, associated with a significant decline in ∆ψm. In addition, tau phosphorylation elevated in the brainstem of hypoxic groups. On the other hand, the power of rhythms declined significantly in the preBötC of hypoxic rats, parallel with changes in the respiratory rate, total respiration time, and expiration time. Moreover, there was a positive and statistically significant correlation between LFP rhythm’s power and inspiration time. Our data showed that besides CSH, aging also contributed to mitochondrial dysfunction, tau hyperphosphorylation, LFP rhythms’ power decline, and changes in respiratory factors.

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Data Availability

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

AD:

Alzheimer’s disease

preBötC:

The pre-Bötzinger complex

VLM:

Ventrolateral medulla

CSH:

Chronic sustained hypoxia

ROS:

Reactive oxygen species

dEMG:

Diaphragm muscle electromyography

LFP:

Local field potential

MMP:

Mitochondrial membrane potential

MAP:

Microtubule-associated protein

GSK3β:

Glycogen synthase kinase-3β

CDK5:

Cyclin-dependent kinase 5

NFTs:

Neurofibrillary tangles

PHF:

Paired helical filaments

CIH:

Chronic intermittent hypoxia

OSAS:

Obstructive sleep apnea syndrome

PP2A:

Protein phosphatase A2

VRG:

Ventral respiratory group

rVRG:

Ventral respiratory group, rostral part

EEG:

Electroencephalography

4V:

Fourth ventricle

Sp5:

Spinal trigeminal tract

Sp5I:

Interpolar nucleus of spinal trigeminal nucleus

AmbC:

Compact part of the ambiguous nucleus

12N:

Hypoglossal nucleus

NTS:

Nucleus tractus solitarius

IOD:

Inferior olive dorsal nucleus

IOPr:

Inferior olive principal nucleus

IOM:

Inferior olive medial nucleus

py:

Pyramidal tract

IF:

Immunofluorescence

mtDNA:

Mitochondrial DNA

PHFD:

Post hypoxic frequency decline

VAH:

Ventilatory acclimatization to hypoxia

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Acknowledgements

The authors would like to express their gratitude to Pouran Karimi for her assistance in molecular analysis. Our data were derived from the thesis of Jamal Khalilpour for a Ph.D. degree in physiology.

Funding

This work was supported by grants (No. 65698) from Drug Applied Research Center, Tabriz University of Medical Science.

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Authors and Affiliations

  1. Drug Applied Research Center, Tabriz University of Medical Sciences, Golgasht Street, Tabriz, East Azerbaijan, Iran

    Jamal Khalilpour, Mohammad Reza Alipour, Zohre Zavari & Parviz Shahabi

  2. Department of Physiology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran

    Firouz Qaderi Pakdel

  3. Department of Neuroscience, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Golgasht Street, Tabriz, East Azerbaijan, Iran

    Hamid Soltani Zangbar

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  1. Jamal Khalilpour
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  2. Hamid Soltani Zangbar
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  3. Mohammad Reza Alipour
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  4. Firouz Qaderi Pakdel
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  5. Zohre Zavari
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  6. Parviz Shahabi
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Contributions

JK and PS conceived the study and designed the experiments. JK wrote the manuscript. JK, PS, and HSZ performed the experiments with the help of ZZ. JK, PS, HSZ, MRA, and FQP interpreted data and contributed to the discussion. All authors reviewed and concurred with the final manuscript. PS takes responsibility for the integrity of the data and the accuracy of the data analysis.

Corresponding authors

Correspondence to Hamid Soltani Zangbar or Parviz Shahabi.

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Ethics Approval

All procedures and handling techniques were approved by the Ethical Committee for Animal Research of Tabriz University of Medical Sciences (IR.TBZMED.VCR.REC.1399.404), and surgical procedures were conducted under aseptic conditions.

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Khalilpour, J., Zangbar, H.S., Alipour, M.R. et al. Chronic Sustained Hypoxia Leads to Brainstem Tauopathy and Declines the Power of Rhythms in the Ventrolateral Medulla: Shedding Light on a Possible Mechanism. Mol Neurobiol 61, 3121–3143 (2024). https://doi.org/10.1007/s12035-023-03763-4

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