Sleep is bi-directionally modified by amyloid beta oligomers

Disrupted sleep is a major feature of Alzheimer’s disease (AD), often arising years before symptoms of cognitive decline. Prolonged wakefulness exacerbates the production of amyloid-beta (Aβ) species, a major driver of AD progression, suggesting that sleep loss further accelerates AD through a vicious cycle. However, the mechanisms by which Aβ affects sleep are unknown. We demonstrate in zebrafish that Aβ acutely and reversibly enhances or suppresses sleep as a function of oligomer length. Genetic disruptions revealed that short Aβ oligomers induce acute wakefulness through Adrenergic receptor b2 (Adrb2) and Progesterone membrane receptor component 1 (Pgrmc1), while longer Aβ forms induce sleep through a pharmacologically tractable Prion Protein (PrP) signaling cascade. Our data indicate that Aβ can trigger a bi-directional sleep/wake switch. Alterations to the brain’s Aβ oligomeric milieu, such as during the progression of AD, may therefore disrupt sleep via changes in acute signaling events.

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Sleep is bi-directionally modified by amyloid beta oligomers

10.1101/610014 ◽

2019 ◽

Cited By ~ 1

Author(s):

Güliz Gürel Özcan ◽

Sumi Lim ◽

Patricia L.A. Leighton ◽

W. Ted Allison ◽

Jason Rihel

Keyword(s):

Prion Protein ◽

Amyloid Beta ◽

Adrenergic Receptor ◽

List Type ◽

Vicious Cycle ◽

Aβ Oligomers ◽

Binding Partners ◽

Receptor Component ◽

Signalling Cascade

SUMMARYDisrupted sleep is a major feature of Alzheimer’s Disease (AD), often arising years before symptoms of cognitive decline. Prolonged wakefulness exacerbates the production of amyloid-beta (Aβ) species, a major driver of AD progression, suggesting that sleep loss further accelerates AD through a vicious cycle. However, the mechanisms by which Aβ affects sleep are unknown. We demonstrate in zebrafish that Aβ acutely and reversibly enhances or suppresses sleep as a function of oligomer length. Genetic disruptions revealed that short Aβ oligomers induce acute wakefulness through Adrenergic receptor b2 (Adrb2) and Progesterone membrane receptor component 1 (Pgrmc1), while longer Aβ forms induce sleep through a pharmacologically tractable Prion Protein (PrP) signalling cascade. Our data indicate that Aβ can trigger a bi-directional sleep/wake switch. Alterations to the brain’s Aβ oligomeric milieu, such as during the progression of AD, may therefore disrupt sleep via changes in acute signalling events.HIGHLIGHTSAmyloid beta oligomers can drive either sleep or wakefulness, depending on their sizeWakefulness driven by short amyloid beta oligomers requires binding partners Adrenergic Beta Receptor 2 and Pgrmc1Long amyloid beta oligomers drive sleep through interaction with Prion ProteinThe in vivo sleep effects of amyloid beta can be pharmacologically blocked by targeting several steps of the Amyloid beta-Prion Protein signalling cascade.

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Faculty Opinions recommendation of The inhalation anesthetic isoflurane induces a vicious cycle of apoptosis and amyloid beta-protein accumulation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1068822.521759 ◽

2007 ◽

Author(s):

Emery Brown

Keyword(s):

Amyloid Beta ◽

Protein Accumulation ◽

Amyloid Beta Protein ◽

Vicious Cycle ◽

Inhalation Anesthetic

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Faculty Opinions recommendation of Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1158625.619545 ◽

2009 ◽

Author(s):

Gerald Zamponi

Keyword(s):

Synaptic Plasticity ◽

Prion Protein ◽

Amyloid Beta ◽

Cellular Prion Protein

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Electrical characteristics of amyloid beta peptides in vertical junctions

NPG Asia Materials ◽

10.1038/s41427-021-00321-z ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Sohyeon Seo ◽

Jinju Lee ◽

Jungsue Choi ◽

G. Hwan Park ◽

Yeseul Hong ◽

...

Keyword(s):

Electron Transfer ◽

Electron Transport ◽

Amyloid Beta ◽

Field Effect Transistors ◽

Brain Diseases ◽

Electrical Characteristics ◽

Transport Pathway ◽

Sequence Dependence ◽

Aβ Oligomers ◽

Aβ Peptides

AbstractAssembled amyloid beta (Aβ) peptides have been considered pathological assemblies involved in human brain diseases, and the electron transfer or electron transport characteristics of Aβ are important for the formation of structured assemblies. Here, we report the electrical characteristics of surface-assembled Aβ peptides similar to those observed in Alzheimer’s patients. These characteristics correlate to their electron transfer characteristics. Electrical current–voltage plots of Aβ vertical junction devices show the Aβ sequence dependence of the current densities at both Aβ monomers (mono-Aβs) and Aβ oligomers (oli-Aβs), while Aβ sequence dependence is not clearly observed in the electrical characteristics of Aβ planar field effect transistors (FETs). In particular, surface oligomerization of Aβ peptides drastically decreases the activity of electron transfer, which presents a change in the electron transport pathway in the Aβ vertical junctions. Electron transport at oli-Aβ junctions is symmetric (tunneling/tunneling) due to the weak and voltage-independent coupling of the less redox-reactive oli-Aβ to the contacts, while that at mono-Aβ junctions is asymmetric (hopping/tunneling) due to redox levels of mono-Aβ voltage-dependently coupled with contact electrodes. Consequently, through vertical junctions, the sequence- and conformation-dependent electrical characteristics of Aβs can reveal their electron transfer activities.

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