FOREBRAIN ALZHEIMER'S DISEASE PATHOLOGY DOES NOT RESULT IN DISORDERED BREATHING IN MICE
Authors: Shi Huanan , Morales Fatima Beatriz Saldana , Martinez Vena Kay , Jankowsky Joanna Louisa , Ray Russell Scott 
Published: June 2021

Alzheimer's disease (AD) is a chronic neurodegenerative disease. Early presentation starts with short‐term memory loss that progresses to disorientation and dementia until key bodily functions fail leading to death. It has become clear that a strong association exists between the onset and progression of AD and sleep disordered breathing such as sleep apnea. Additionally, studies in rodent AD and tauopathy models show perturbations to respiratory homeostasis. However, it remains unclear how AD pathophysiology and disordered breathing may interact to exacerbate disease progression. Thus, a better understanding of the relationship between AD progression and respiratory homeostasis is needed.

To determine if disordered respiratory dysfunction was a feature in an Alzheimer's mouse model, we aimed to assess respiratory function over multiple time points in a transgenic amyloid precursor protein overexpression mouse model. In these mice, mutated amyloid precursor protein (APP (swe/ind)) expression is under the control of a tetracycline‐responsive promoter that is activated by the CaMKII‐tetracycline transactivator (TTA) driver. Removal of doxycycline (dox) from the diet results in constitutive APP expression. Previous studies have shown that expression of the TTA driver and plaque pathology are largely focused in the forebrain and midbrain while sparing the brainstem, providing the ability to focus on forebrain and midbrain pathology in respiratory function.

Experimental mice (APP/TTA) and three groups of sibling control mice (APP only, TTA only and WT mice) were assessed for baseline respiratory and chemosensory function as well as acute metabolic rate approximately every two months. Here we report the result from three key time points; 1) at four months after dox removal, immediately prior to histopathology onset; 2) at 13 months of age following 9 months of transgenic APP expression when cognitive impairment is pronounced; and 3) at the terminal time point of 23 months of age following 21 months of APP expression when histopathology is severe. Mice were analyzed for respiratory rate (Vf), tidal volume (VT), minute ventilation (VE), oxygen consumption (VO2), and (VE/VO2).

Using two‐way ANOVA, we did not find any significant differences between experimental group and control groups with the exception of a difference in Vf between amyloid‐bearing APP/TTA mice and single transgenic APPcontrol mice at 13 months of age. Additionally, we saw significant differences in respiratory output between single transgenic APP control and WT as well as single transgenic TTA control and WT in VE/VO2. Results demonstrate that forebrain AD pathology in this mouse model is insufficient to consistently alter respiratory homeostasis. Notably, forebrain perturbations and injuries, including seizures and strokes, can result in acute and chronic breathing irregularities. However, our results suggest that disordered breathing associated with AD progression may stem from direct effects on brainstem or peripheral circuits.

Support or Funding Information

McNair Medical Institute, Baylor College of Medicine Memory Brain Research Center Seed Award

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.