Dataset Information

Disruption of the sleep-wake cycle and diurnal fluctuation of ?-amyloid in mice with Alzheimer's disease pathology.

ABSTRACT: Aggregation of ?-amyloid (A?) in the brain begins to occur years before the clinical onset of Alzheimer's disease (AD). Before A? aggregation, concentrations of extracellular soluble A? in the interstitial fluid (ISF) space of the brain, which are regulated by neuronal activity and the sleep-wake cycle, correlate with the amount of A? deposition in the brain seen later. The amount and quality of sleep decline with normal aging and to a greater extent in AD patients. How sleep quality as well as the diurnal fluctuation in A? change with age and A? aggregation is not well understood. We report a normal sleep-wake cycle and diurnal fluctuation in ISF A? in the brain of the APPswe/PS1?E9 mouse model of AD before A? plaque formation. After plaque formation, the sleep-wake cycle markedly deteriorated and diurnal fluctuation of ISF A? dissipated. As in mice, diurnal fluctuation of cerebrospinal fluid A? in young adult humans with presenilin mutations was also markedly attenuated after A? plaque formation. Virtual elimination of A? deposits in the mouse brain by active immunization with A?(42) normalized the sleep-wake cycle and the diurnal fluctuation of ISF A?. These data suggest that A? aggregation disrupts the sleep-wake cycle and diurnal fluctuation of A?. Sleep-wake behavior and diurnal fluctuation of A? in the central nervous system may be functional and biochemical indicators, respectively, of A?-associated pathology.

SUBMITTER: Roh JH

PROVIDER: S-EPMC3654377 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Disruption of the sleep-wake cycle and diurnal fluctuation of β-amyloid in mice with Alzheimer's disease pathology.

Roh Jee Hoon JH Huang Yafei Y Bero Adam W AW Kasten Tom T Stewart Floy R FR Bateman Randall J RJ Holtzman David M DM

Science translational medicine 20120901 150

Aggregation of β-amyloid (Aβ) in the brain begins to occur years before the clinical onset of Alzheimer's disease (AD). Before Aβ aggregation, concentrations of extracellular soluble Aβ in the interstitial fluid (ISF) space of the brain, which are regulated by neuronal activity and the sleep-wake cycle, correlate with the amount of Aβ deposition in the brain seen later. The amount and quality of sleep decline with normal aging and to a greater extent in AD patients. How sleep quality as well as ...[more]

PMID: 22956200

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Project description:Sleep is critical for hippocampus-dependent memory consolidation. However, the underlying mechanisms of synaptic plasticity are poorly understood. The central controversy is on whether long-term potentiation (LTP) takes a role during sleep and which would be its specific effect on memory. To address this question, we used immunohistochemistry to measure phosphorylation of Ca2+/calmodulin-dependent protein kinase II (pCaMKIIα) in the rat hippocampus immediately after specific sleep-wake states were interrupted. Control animals not exposed to novel objects during waking (WK) showed stable pCaMKIIα levels across the sleep-wake cycle, but animals exposed to novel objects showed a decrease during subsequent slow-wave sleep (SWS) followed by a rebound during rapid-eye-movement sleep (REM). The levels of pCaMKIIα during REM were proportional to cortical spindles near SWS/REM transitions. Based on these results, we modeled sleep-dependent LTP on a network of fully connected excitatory neurons fed with spikes recorded from the rat hippocampus across WK, SWS and REM. Sleep without LTP orderly rescaled synaptic weights to a narrow range of intermediate values. In contrast, LTP triggered near the SWS/REM transition led to marked swaps in synaptic weight ranking. To better understand the interaction between rescaling and restructuring during sleep, we implemented synaptic homeostasis and embossing in a detailed hippocampal-cortical model with both excitatory and inhibitory neurons. Synaptic homeostasis was implemented by weakening potentiation and strengthening depression, while synaptic embossing was simulated by evoking LTP on selected synapses. We observed that synaptic homeostasis facilitates controlled synaptic restructuring. The results imply a mechanism for a cognitive synergy between SWS and REM, and suggest that LTP at the SWS/REM transition critically influences the effect of sleep: Its lack determines synaptic homeostasis, its presence causes synaptic restructuring.

Dataset Information

Disruption of the sleep-wake cycle and diurnal fluctuation of ?-amyloid in mice with Alzheimer's disease pathology.

Publications

Disruption of the sleep-wake cycle and diurnal fluctuation of β-amyloid in mice with Alzheimer's disease pathology.

Similar Datasets

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