Amyloid beta plaque pathology induces chemosensory deficits and increases apnoeas in the 5XFAD mouse model of Alzheimer's disease.

Sleep disordered breathing (SDB) commonly co-presents with other ventilatory impairments in patients with Alzheimer's disease (AD). Typically reported as either obstructive (OSA) or complex sleep apnoea in AD patients, SDB results in repeated bouts of hypoxia and hypercapnia from insufficient ventilation. It is thought not only that these repeated hypoxic events result in an exacerbation of AD but also that SDB and other ventilatory impairments may be a precursor to neurodegenerative diseases. Although the cause of SDB in AD patients is unclear, chemosensory drive malfunction, a response critical to maintaining homeostatic oxygen and carbon dioxide balance, may play a role. We examined basal ventilation, SDB and chemosensory function in 5XFAD mice, a beta amyloidosis model of AD which displays progressive amyloid beta (Aβ) plaque deposition by 8 months of age. We found that both male and female 5XFAD mice had nearly twice as many spontaneous apnoeas per hour compared to WT mice. Basal ventilation (V̇E) and air convection requirement (ACR) while awake were unchanged, but both hypoxic and hypercapnic ventilatory responses were impaired in 5XFAD mice. While WT mice responded to acute hypoxia with the expected increase in V̇E of ∼150%, 5XFAD mice showed a blunted increase of ∼70% with a similarly blunted hypercapnic response (∼100% increase in 5XFAD mice/∼200% increase in WT mice). Further, we found substantial Aβ deposition in the ventral lateral medulla, an important site for rhythm generation and chemosensing. Taken together, these data suggest a correlation between SDB, Aβ deposition and chemosensory deficits in 5XFAD mice. KEY POINTS: Respiratory dysfunction is common among Alzheimer's disease (AD) patients, but the nature of this dysfunction is not well understood Sleep disordered breathing (SDB) is prevalent in AD patients and is thought to contribute to disease progression 5XFAD mice, a model of beta amyloidosis, display similar respiratory deficits to humans with AD, including SDB and chemosensory changes We show that amyloid beta plaque deposition in the brainstem of 5XFAD mice localizes to regions of respiratory control Our data suggest that amyloid beta plaque deposition in brainstem respiratory control regions contributes to chemosensory dysfunction in 5XFAD mice, a pathology that could worsen SDB occurrence and potentially Aβ-dependent neuropathologies such as AD.