Progressive Tauopathy Disrupts Breathing Pattern during Presumptive Sleep
Authors List
Alexandria B. Marciante1, Jada Lewis2, Gordon S. Mitchell1
1Breathing Research and Therapeutics Center, Department of Physical Therapy
2Center for Translational Research in Neurodegenerative Diseases, Department of Neuroscience McKnight Brain Institute, University of Florida, Gainesville, FL, USA 32610
Rationale
Sleep apnea occurs in over 50% of individuals with Alzheimer’s Disease (AD) or related Tauopathies. While there have been investigations into sleep apnea and its potential to exacerbate AD, less is known concerning the role of progressive, age-related Tauopathy in the pathogenesis of sleep disordered breathing. In this study, we tested the hypotheses that the rTg4510 murine model of Tauopathy: 1) exhibits breathing instability during presumptive sleep that is exacerbated with aging, reflecting the progression of Tauopathy and 2) that progressive Tauopathy impairs chemoreflex function during presumptive sleep.
Methods
The rTg4510 mice progressively develop severe Tauopathy in the hippocampus and cortex, with Tauopathy extending to other brain regions with aging. Type I and II post-sigh apnea, Type III (spontaneous) apnea, sigh and hypopnea incidence were measured in young (5-6 months; n=10-14/group) and aged (13-15 months; n=22-24/group) non-transgenic (nTg), monogenic control (tTA), and bigenic rTg4510 mice using whole-body plethysmography during presumptive sleep, or “quiet rest” (i.e. eyes closed, curled/laying posture, stable breathing for > 200 breaths) in ambient conditions (21% O2). Chemoreceptor sensitivity was assessed using transient exposures (5 min) to hyperoxia (100% O2) or hypercapnia (3% and 5% CO2, 21% O2).
Results
We report significant increases in Type I, II and III apneas (all p<0.001), sighs (p=0.002) and hypopneas (p<0.001) in aged rTg4510 mice, but only Type III apneas in young rTg4510 mice (p<0.001) vs age-matched nTg mice. Unlike aged nTg and tTA mice, aged rTg4510 mice exhibited impaired chemoreflex sensitivity; in rTg4510 mice, there were no significant changes in breathing frequency, tidal volume or minute ventilation during hyperoxic or hypercapnic challenges vs baseline, in striking contrast with non-transgenic controls. There were no differences in outcome measurements between non-transgenic or monogenic control mice at either age. No significant sex differences were observed within or between genotypes. In preliminary histological examination, hyperphosphorylated Tau was observed in brainstem regions known to be either directly or indirectly involved in respiratory control (e.g., pontine respiratory group, medullary respiratory groups, retrotrapezoid nucleus) in aged rTg4510 mice. In contrast, similar extent of breathing instability or brainstem hyperphosphorylated Tau were not observed in young rTg4510 mice.
Conclusion
We report impaired breathing function, progressively higher incidences of Type I-III apneas, hypopneas and sighs, and diminished chemoreflex sensitivity in old rTg4510 mice vs nTg and tTA controls. These findings reflect progressive Tauopathy expanding into brainstem regions known to control breathing. Tau pathology in these brain regions is also observed in human Tauopathy. Thus, Tauopathy in this model may directly contribute to the impaired chemoreflexes and the development of sleep-disordered breathing.
Funding. This work was supported by Florida Department of Health (FDOH) Ed & Ethel Moore Alzheimer’s Research Program (PI: GSM; Co-I: JL), NIH T32HL134621-5 (ABM), and the UF Brain Spinal Cord Research Trust Fund.
Alexandria B. Marciante1, Jada Lewis2, Gordon S. Mitchell1
1Breathing Research and Therapeutics Center, Department of Physical Therapy
2Center for Translational Research in Neurodegenerative Diseases, Department of Neuroscience McKnight Brain Institute, University of Florida, Gainesville, FL, USA 32610
Rationale
Sleep apnea occurs in over 50% of individuals with Alzheimer’s Disease (AD) or related Tauopathies. While there have been investigations into sleep apnea and its potential to exacerbate AD, less is known concerning the role of progressive, age-related Tauopathy in the pathogenesis of sleep disordered breathing. In this study, we tested the hypotheses that the rTg4510 murine model of Tauopathy: 1) exhibits breathing instability during presumptive sleep that is exacerbated with aging, reflecting the progression of Tauopathy and 2) that progressive Tauopathy impairs chemoreflex function during presumptive sleep.
Methods
The rTg4510 mice progressively develop severe Tauopathy in the hippocampus and cortex, with Tauopathy extending to other brain regions with aging. Type I and II post-sigh apnea, Type III (spontaneous) apnea, sigh and hypopnea incidence were measured in young (5-6 months; n=10-14/group) and aged (13-15 months; n=22-24/group) non-transgenic (nTg), monogenic control (tTA), and bigenic rTg4510 mice using whole-body plethysmography during presumptive sleep, or “quiet rest” (i.e. eyes closed, curled/laying posture, stable breathing for > 200 breaths) in ambient conditions (21% O2). Chemoreceptor sensitivity was assessed using transient exposures (5 min) to hyperoxia (100% O2) or hypercapnia (3% and 5% CO2, 21% O2).
Results
We report significant increases in Type I, II and III apneas (all p<0.001), sighs (p=0.002) and hypopneas (p<0.001) in aged rTg4510 mice, but only Type III apneas in young rTg4510 mice (p<0.001) vs age-matched nTg mice. Unlike aged nTg and tTA mice, aged rTg4510 mice exhibited impaired chemoreflex sensitivity; in rTg4510 mice, there were no significant changes in breathing frequency, tidal volume or minute ventilation during hyperoxic or hypercapnic challenges vs baseline, in striking contrast with non-transgenic controls. There were no differences in outcome measurements between non-transgenic or monogenic control mice at either age. No significant sex differences were observed within or between genotypes. In preliminary histological examination, hyperphosphorylated Tau was observed in brainstem regions known to be either directly or indirectly involved in respiratory control (e.g., pontine respiratory group, medullary respiratory groups, retrotrapezoid nucleus) in aged rTg4510 mice. In contrast, similar extent of breathing instability or brainstem hyperphosphorylated Tau were not observed in young rTg4510 mice.
Conclusion
We report impaired breathing function, progressively higher incidences of Type I-III apneas, hypopneas and sighs, and diminished chemoreflex sensitivity in old rTg4510 mice vs nTg and tTA controls. These findings reflect progressive Tauopathy expanding into brainstem regions known to control breathing. Tau pathology in these brain regions is also observed in human Tauopathy. Thus, Tauopathy in this model may directly contribute to the impaired chemoreflexes and the development of sleep-disordered breathing.
Funding. This work was supported by Florida Department of Health (FDOH) Ed & Ethel Moore Alzheimer’s Research Program (PI: GSM; Co-I: JL), NIH T32HL134621-5 (ABM), and the UF Brain Spinal Cord Research Trust Fund.
