TY - JOUR T1 - Progressive Changes in Sleep and Its Relations to Amyloid-β Distribution and Learning in Single <em>App</em> Knock-In Mice JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0093-20.2020 VL - 7 IS - 2 SP - ENEURO.0093-20.2020 AU - Sakura Eri B. Maezono AU - Mika Kanuka AU - Chika Tatsuzawa AU - Miho Morita AU - Taizo Kawano AU - Mitsuaki Kashiwagi AU - Pimpimon Nondhalee AU - Masanori Sakaguchi AU - Takashi Saito AU - Takaomi C. Saido AU - Yu Hayashi Y1 - 2020/03/01 UR - http://www.eneuro.org/content/7/2/ENEURO.0093-20.2020.abstract N2 - Alzheimer’s disease (AD) patients often suffer from sleep disturbances. Alterations in sleep, especially rapid eye movement sleep (REMS), can precede the onset of dementia. To accurately characterize the sleep impairments accompanying AD and their underlying mechanisms using animal models, it is crucial to use models in which brain areas are affected in a manner similar to that observed in the actual patients. Here, we focused on AppNL-G-F mice, in which expression levels and patterns of mutated amyloid precursor protein (APP) follow the endogenous patterns. We characterized the sleep architecture of male AppNL-G-F homozygous and heterozygous mice at two ages (six and 12 months). At six months, homozygous mice exhibited reduced REMS, which was further reduced at 12 months together with a slight reduction in non-REMS (NREMS). By contrast, heterozygous mice exhibited an overall normal sleep architecture. Homozygous mice also exhibited decreased electroencephalogram γ to δ power ratio during REMS from six months, resembling the electroencephalogram slowing phenomenon observed in preclinical or early stages of AD. In addition, homozygous mice showed learning and memory impairments in the trace fear conditioning (FC) at both ages, and task performance strongly correlated with REMS amount at 12 months. Finally, histologic analyses revealed that amyloid-β accumulation in the pontine tegmental area and ventral medulla followed a course similar to that of the REMS reduction. These findings support the notion that changes in REMS are an early marker of AD and provide a starting point to address the mechanism of sleep deficits in AD and the effects on cognition. ER -