Blunted Respiratory Responses in the Streptozotocin-Induced Alzheimer’s Disease Rat Model

Abstract

Alzheimer's disease (AD) is known for the progressive decline of cognition and memory. In addition to these disease-defining symptoms, impairment of respiratory function is frequently observed and often expressed by sleep-disordered breathing or reduced ability to adjust respiration when oxygen demand is elevated. The mechanisms for this are widely unknown. Postmortem analysis from the brainstem of AD patients reveals pathological alterations, including in nuclei responsible for respiratory control. In this study, we analyzed respiratory responses and morphological changes in brainstem nuclei following intracerebroventricular (ICV) injections of streptozotocin (STZ), a rat model commonly used to mimic sporadic AD. ICV-STZ induced significant astrogliosis in the commissural part of the nucleus tractus solitarii, an area highly involved in respiration control. The astrogliosis was identified by a significant increase in S100B-immunofluorescence that is similar to the astrogliosis found in the CA1 region of the hippocampus. Using plethysmography, the control group displayed a typical age-dependent decrease of ventilation that was absent in the STZ rat group. This is indicative of elevated minute ventilation at rest after STZ treatment. Peripheral chemoreflex responses were significantly blunted in STZ rats as seen by a reduced respiratory rate and minute ventilation to hypoxia. Central chemoreflex responses to hypercapnia, on the other hand, only decreased in respiratory rate following STZ treatment. Overall, our results show that ICV-STZ induces respiratory dysfunction at rest and in response to hypoxia. This provides a new tool to study the underlying mechanisms of breathing disorders in clinical AD.

Establishing Reference Cardiorespiratory Fitness Parameters in Alzheimer’s Disease

“…Blunted respiratory response to CPET has been documented previously in persons with AD [4]. however, the mechanisms have only recently began to be explored in animal models [27].…”

Astrocytes in the nucleus of the solitary tract: Contributions to neural circuits controlling physiology

“… Stimulus Outcome Species Reference Ozone inhalation (3 hours) Greater VEGF expression in NTS astrocytes than normoxic controls, increased branching of cells Rat Araneda et al 2008 [63] Ozone inhalation (24 hours) Greater glial coverage of synapses in NTS compared with untreated controls Rat Chounlamountry et al 2015 [64] 10% Oxygen inhalation Greater NTS GFAP immunoreactivity (1 and 6 hours, compared with normoxic controls). 6 hour blocked by minocycline Mouse Tadmouri et al 2014 [60] 10% Oxygen inhalation Greater GFAP immunoreactivity in NTS (4 and 24 hours, compared with normoxic controls), blocked by minocycline Rat Stokes et al 2017 [65] 10% Oxygen inhalation Greater GFAP immunoreactivity in NTS after 10 days compared with normoxic controls Rat De La Zerda et al 2018 [66] Thioacetamine injection (liver damage model) Greater number of GFAP expressing cells in NTS compared with vehicle injected controls Rat Tsai et al 2017 [67] Lateral ventricle STZ treatment (neurodegeneration model) Greater S100b immunoreactivity in commissural NTS compared with vehicle injected controls Rat Ebel et al 2017 [68] Intrastriatal 6-OHDA injection (Parkinsonian model) Lower GFAP immunoreactivity in NTS after 60 days compared with shorter durations Rat Fernandes-Junior et al 2018 [69] Two-kidney 1-clip hypertension Greater number of GFAP-positive pixels in NTS than in normotensive controls Rat Melo et al 2019 [70] Isoproterenol induced water drinking No difference in GFAP immunoreactivity in NTS Rat Hardy et al 2018 [71] Age Greater GFAP immunoreactivity in NTS of aged (24 months) compared with young (6 months) ...…”

“…For example, NTS GFAP immunoreactivity is increased in a pharmacological rat model of liver failure, alongside impaired baroreflex sensitivity in these animals [67] . In a model where streptozotocin (STZ) is infused into the lateral ventricle of rats to induce neurodegeneration, greater s100b-immunoreactivity is seen in the NTS, accompanied by an impaired ability to increase breathing rate to compensate for hypoxia [68] . In another neurodegenerative disease model, 60 days after induction of Parkinsonian neuropathology (following striatal 6-hydroxydopamine injection) rats show decreased NTS GFAP immunoreactivity, which also correlates with respiratory changes [69] .…”

Snoring Remediation with Oral Appliance Therapy Potentially Reverses Cognitive Impairment: An Intervention Controlled Pilot Study

“…AD is now ranked as the sixth leading cause of death in the U.S.A. [ 1 ]. Typically, AD respiratory dysfunction manifests as sleep disordered breathing (SDB) [ 2 ]. The neural network involved in sleep and respiration regulation is complex with known brainstem controlling nuclei.…”