Cholinergic basal forebrain degeneration due to sleep-disordered breathing exacerbates pathology in a mouse model of Alzheimer’s disease

Lei Qian, Oliver Rawashdeh, Leda Kasas, Michael R. Milne, Nicholas Garner, Kornraviya Sankorrakul, Nicola Marks, Matthew W. Dean, Pu Reum Kim, Aanchal Sharma, Mark C. Bellingham and Elizabeth J. Coulson ()
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Lei Qian: The University of Queensland
Oliver Rawashdeh: The University of Queensland
Leda Kasas: The University of Queensland
Michael R. Milne: The University of Queensland
Nicholas Garner: The University of Queensland
Kornraviya Sankorrakul: The University of Queensland
Nicola Marks: The University of Queensland
Matthew W. Dean: The University of Queensland
Pu Reum Kim: The University of Queensland
Aanchal Sharma: The University of Queensland
Mark C. Bellingham: The University of Queensland
Elizabeth J. Coulson: The University of Queensland

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Although epidemiological studies indicate that sleep-disordered breathing (SDB) such as obstructive sleep apnea is a strong risk factor for the development of Alzheimer’s disease (AD), the mechanisms of the risk remain unclear. Here we developed a method of modeling SDB in mice that replicates key features of the human condition: altered breathing during sleep, sleep disruption, moderate hypoxemia, and cognitive impairment. When we induced SDB in a familial AD model, the mice displayed exacerbation of cognitive impairment and the pathological features of AD, including increased levels of amyloid-beta and inflammatory markers, as well as selective degeneration of cholinergic basal forebrain neurons. These pathological features were not induced by chronic hypoxia or sleep disruption alone. Our results also revealed that the cholinergic neurodegeneration was mediated by the accumulation of nuclear hypoxia inducible factor 1 alpha. Furthermore, restoring blood oxygen levels during sleep to prevent hypoxia prevented the pathological changes induced by the SDB. These findings suggest a signaling mechanism whereby SDB induces cholinergic basal forebrain degeneration.

Date: 2022
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DOI: 10.1038/s41467-022-33624-y

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