Combined Effects of Intermittent Hypoxia and Amyloid Beta on Hippocampal Activity, Its Cholinergic Modulation, and Memory

Obstructive sleep apnea (OSA), characterized by repetitive upper airway obstruction, leads to chronic intermittent hypoxia (cIH) and induces cognitive and neuronal network disruptions similar to those observed in Alzheimer's disease (AD). These pathologies are often presented together in the elderly and share some pathophysiological mechanisms. The presence of amyloid beta (Aβ), observed both in AD and OSA patients, can alter brain function, cholinergic modulation and memory either independently or in addition with cIH. To explore these possibilities, we studied the pathological effects of Aβ, cIH, and their combination on cognition and hippocampal activity, and its modulations by the cholinomimetics carbachol, muscarine, and nicotine, along with evaluations of choline acetyltransferase (ChAT) expression in the septum and the hippocampus. We found that cIH and Aβ similarly affect spatial memory and additively impact aversive memory (sparing recognition memory). Although cIH and Aβ share some pathological effects on hippocampal activity and its modulation by cholinomimetics, when combined, they produce an additive inhibition at the population and single-cell levels more evident in the presence of nicotine. No change in ChAT expression was observed. Remarkably, the departure from normal firing as well as the disruption of carbachol-induced response correlates with the reduction of aversive memory in our experimental groups. In summary, cIH and Aβ share pathological effects, but their combination exacerbates functional pathology, contributing to our understanding of AD/OSA pathophysiology and co-morbidity.