Sleep is bi-directionally modified by amyloid beta oligomers

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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Sleep is bi-directionally modified by amyloid beta oligomers

eLife ◽

10.7554/elife.53995 ◽

2020 ◽

Vol 9 ◽

Author(s):

Güliz Gürel Özcan ◽

Sumi Lim ◽

Patricia LA Leighton ◽

W Ted Allison ◽

Jason Rihel

Keyword(s):

Cognitive Decline ◽

Prion Protein ◽

Amyloid Beta ◽

Adrenergic Receptor ◽

Sleep Loss ◽

Membrane Receptor ◽

Signaling Cascade ◽

Vicious Cycle ◽

Aβ Oligomers ◽

Receptor Component

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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The genetic landscape for amyloid beta fibril nucleation accurately discriminates familial Alzheimer’s disease mutations

10.1101/2020.09.22.308429 ◽

2020 ◽

Cited By ~ 1

Author(s):

Mireia Seuma ◽

Andre Faure ◽

Marta Badia ◽

Ben Lehner ◽

Benedetta Bolognesi

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Beta ◽

Amyloid Fibrils ◽

List Type ◽

Familial Alzheimer’S Disease ◽

Disease Mutations ◽

Genetic Landscape ◽

Familial Alzheimer's Disease

AbstractAmyloid fibrils are associated with many human diseases but how mutations alter the propensity of proteins to form fibrils has not been comprehensively investigated and is not well understood. Alzheimer’s Disease (AD) is the most common form of dementia with amyloid plaques of the amyloid beta (Aß) peptide a pathological hallmark of the disease. Mutations in Aß also cause familial forms of AD (fAD). Here we use deep mutational scanning to quantify the effects of >14,000 mutations on the aggregation of Aß. The resulting genetic landscape reveals fundamental mechanistic insights into fibril nucleation, including the importance of charge and gatekeeper residues in the disordered region outside of the amyloid core in preventing nucleation. Strikingly, unlike computational predictors and previous measurements, the in vivo nucleation scores accurately identify all known dominant fAD mutations, validating this simple cell-based assay as highly relevant to the human genetic disease and suggesting accelerated fibril nucleation is the ultimate cause of fAD. Our results provide the first comprehensive map of how mutations alter the formation of any amyloid fibril and a validated resource for the interpretation of genetic variation in Aß.HighlightsFirst comprehensive map of how mutations alter the propensity of a protein to form amyloid fibrils.Charge and gatekeeper residues in the disordered N-terminus of amyloid beta prevent fibril nucleation.Rates of nucleation in a cell-based assay accurately identify the mutations that cause dominant familial Alzheimer’s disease.The combination of deep mutational scanning and human genetics provides a general strategy to quantify the disease-relevance of in vitro and in vivo assays.

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Amyloid beta oligomers modulate neuronal autophagy through the primary cilium

10.1101/2021.06.02.446758 ◽

2021 ◽

Author(s):

Olatz Pampliega ◽

Federico N. Soria ◽

Narayana Pineda-Ramirez ◽

Erwan Bezard

Keyword(s):

Neurodegenerative Diseases ◽

Amyloid Beta ◽

Primary Cilium ◽

Adult Brain ◽

Dependent Manner ◽

Aβ Oligomers ◽

App Processing ◽

Age Dependent ◽

Aβ Generation

The major neurodegenerative diseases, like Alzheimer disease (AD), accumulate neuropathogenic proteins that compromise autophagic function. In AD, autophagy contributes to intracellular APP processing and amyloid beta (Aβ) generation by mutant presenilin-1 (PS1). However, how extracellular soluble Aβ oligomers (Aβo) impact intracellular autophagy is not well understood. The primary cilium (PC), a signaling organelle on the surface of mature neurons and glia, is able to bind Aβ. Since PC signaling pathways knowingly modify autophagy in non-brain cells, we here investigated the role of neuronal PC in the modulation of autophagy during acute extracellular Aβo overload. Our results show that, in vivo, recombinant Aβo require the presence of neuronal PC to modulate early autophagy and to induce the accumulation of autophagic vacuoles in an age-dependent manner. We show that activated Akt mediates these effects in an age-dependent manner, and that ciliary p75NTR receptor is required to block autophagy by Aβo. These findings demonstrate that neuronal PC in the adult brain participates in the deleterious effects mediated by soluble Aβo. The PC should therefore be considered as a target organelle to modulate autophagy for the treatment of neurodegenerative diseases.

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The inhibition of cellular toxicity of amyloid-beta by dissociated transthyretin

10.1101/852715 ◽

2019 ◽

Author(s):

Qin Cao ◽

Daniel H. Anderson ◽

Wilson Liang ◽

Joshua Chou ◽

Lorena Saelices

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Beta ◽

Amyloid Plaques ◽

Inhibitory Effect ◽

Aβ Oligomers ◽

Transthyretin Amyloidosis ◽

Cellular Toxicity ◽

Aβ Aggregation

AbstractThe protective effect of transthyretin (TTR) on cellular toxicity of amyloid-beta (Aβ) has been previously reported. TTR is a tetrameric carrier of thyroxine in blood and cerebrospinal fluid, whose pathogenic aggregation causes systemic amyloidosis. In contrast, many reports have shown that TTR binds amyloid-beta (Aβ), associated with Alzheimer’s disease, alters its aggregation, and inhibits its toxicity both in vitro and in vivo. In this study, we question whether TTR amyloidogenic ability and its anti-amyloid inhibitory effect are associated. Our results indicate that the dissociation of the TTR tetramer, required for its amyloid pathogenesis, is also necessary to prevent cellular toxicity from Aβ oligomers. These findings suggest that the Aβ binding site of TTR may be hidden in its tetrameric form. Aided by computational docking and peptide screening, we identified a TTR segment that is capable of altering Aβ aggregation and toxicity, mimicking TTR cellular protection. This segment inhibits Aβ oligomer formation and also promotes the formation of non-toxic, non-amyloid, amorphous aggregates which are more sensitive to protease digestion. This segment also inhibits seeding of Aβ catalyzed by Aβ fibrils extracted from the brain of an Alzheimer’s patient. Our results suggest that mimicking the inhibitory effect of TTR with peptide-based therapeutics represents an additional avenue to explore for the treatment of Alzheimer’s disease.Significance statementThe pathological landmarks of Alzheimer’s disease are the formation of amyloid plaques and neurofibrillary tangles. Amyloid plaques contain fibrous structures made of aggregated amyloid-beta (Aβ). In 1982, Shirahama and colleagues observed the presence of transthyretin (TTR) in these plaques. TTR is a tetrameric protein whose aggregation causes transthyretin amyloidosis. However, TTR protects Aβ from aggregating and causing toxicity to neurons. In this study, we show that the dissociation of TTR tetramers is required to inhibit cellular toxicity caused by Aβ. In addition, we identified a minimum segment of TTR that inhibits Aβ aggregation and cellular toxicity by the formation of amorphous aggregates that are sensitive to proteases, similar to the natural effect of TTR found by others in vivo.

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LACK OF EFFECT OF CORTICOSTEROIDS ON THE IN VIVO DISAPPEARANCE OF SULFHYDRYL-INHIBITED AND ANTIBODY-COATED ERYTHROCYTES

Acta Endocrinologica ◽

10.1530/acta.0.047s028 ◽

1964 ◽

Vol 47 (3_Suppl) ◽

pp. S28-S36

Author(s):

Kailash N. Agarwal

Keyword(s):

Red Cells ◽

List Type ◽

Red Cell

ABSTRACT Red cells were incubated in vitro with sulfhydryl inhibitors and Rhantibody with and without prior incubation with prednisolone-hemisuccinate. These erythrocytes were labelled with Cr51 and P32 and their disappearance in vivo after autotransfusion was measured. Prior incubation with prednisolone-hemisuccinate had no effect on the rate of red cell disappearance. The disappearance of the cells was shown to take place without appreciable intravascular destruction.

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STUDIES IN CONGENITAL GENERALIZED LIPODYSTROPHY

Acta Endocrinologica ◽

10.1530/acta.0.0720495 ◽

1973 ◽

Vol 72 (3) ◽

pp. 495-505 ◽

Cited By ~ 7

Author(s):

Oddmund Søvik ◽

Svein Oseid

Keyword(s):

Biological Activity ◽

Insulin Response ◽

Epididymal Adipose Tissue ◽

Large Individual ◽

Immunoreactive Insulin ◽

List Type ◽

Glucose Load ◽

Congenital Generalized Lipodystrophy ◽

The One

ABSTRACT The biological activity of plasma insulin from 4 cases of congenital generalized lipodystrophy has been studied, using rat diaphragm and epididymal adipose tissue in vivo. The results are compared with previous data on plasma immunoreactive insulin obtained in these patients. 2 of the 4 cases exhibited unusually high biological insulin activities during the fasting state as well as after an intravenous (iv) glucose load. In the fat pad assay activities as high as 10 000 μU insulin per ml were observed. During childhood the biological insulin activities were generally high, although there were large individual variations. However, in the one case studied after the age of puberty, the insulin response to a glucose load was negligible. Taken together, the biological and immunological activities observed strongly suggest the presence of pancreatic insulin in these patients. It appears that the circulating insulin has a fully biological activity. The decreasing insulin activities after cessation of growth are in agreement with the appearance of frank diabetes at this time.

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Rapid, Refined, and Robust Method for Expression, Purification, and Characterization of Recombinant Human Amyloid-beta M1-42

10.26434/chemrxiv.7725002.v1 ◽

2019 ◽

Author(s):

Priya Prakash ◽

Travis Lantz ◽

Krupal P. Jethava ◽

Gaurav Chopra

Keyword(s):

Amyloid Beta ◽

Western Blots ◽

Force Microscopy ◽

E Coli ◽

Atomic Force ◽

Set Up ◽

Short Time

Amyloid plaques found in the brains of Alzheimer’s disease (AD) patients primarily consists of amyloid beta 1-42 (Ab42). Commercially, Ab42 is synthetized using peptide synthesizers. We describe a robust methodology for expression of recombinant human Ab(M1-42) in Rosetta(DE3)pLysS and BL21(DE3)pLysS competent E. coli with refined and rapid analytical purification techniques. The peptide is isolated and purified from the transformed cells using an optimized set-up for reverse-phase HPLC protocol, using commonly available C18 columns, yielding high amounts of peptide (~15-20 mg per 1 L culture) in a short time. The recombinant Ab(M1-42) forms characteristic aggregates similar to synthetic Ab42 aggregates as verified by western blots and atomic force microscopy to warrant future biological use. Our rapid, refined, and robust technique to purify human Ab(M1-42) can be used to synthesize chemical probes for several downstream in vitro and in vivo assays to facilitate AD research.

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