Diets with Higher ω-6/ω-3 Ratios Show Differences in Ceramides and Fatty Acid Levels Accompanied by Increased Amyloid-Beta in the Brains of Male APP/PS1 Transgenic Mice

Senile plaque formation as a consequence of amyloid-β peptide (Aβ) aggregation constitutes one of the main hallmarks of Alzheimer’s disease (AD). This pathology is characterized by synaptic alterations and cognitive impairment. In order to either prevent or revert it, different therapeutic approaches have been proposed, and some of them are focused on diet modification. Modification of the ω-6/ω-3 fatty acids (FA) ratio in diets has been proven to affect Aβ production and senile plaque formation in the hippocampus and cortex of female transgenic (TG) mice. In these diets, linoleic acid is the main contribution of ω-6 FA, whereas alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA) are the contributors of ω-3 FA. In the present work, we have explored the effect of ω-6/ω-3 ratio modifications in the diets of male double-transgenic APPswe/PS1ΔE9 (AD model) and wild-type mice (WT). Amyloid burden in the hippocampus increased in parallel with the increase in dietary ω-6/ω-3 ratio in TG male mice. In addition, there was a modification in the brain lipid profile proportional to the ω-6/ω-3 ratio of the diet. In particular, the higher the ω-6/ω-3 ratio, the lower the ceramides and higher the FAs, particularly docosatetraenoic acid. Modifications to the cortex lipid profile was mostly similar between TG and WT mice, except for gangliosides (higher levels in TG mice) and some ceramide species (lower levels in TG mice).

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Monomeric and fibrillar α-synuclein exert opposite effects on the catalytic cycle that promotes the proliferation of Aβ42 aggregates

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1700239114 ◽

2017 ◽

Vol 114 (30) ◽

pp. 8005-8010 ◽

Cited By ~ 16

Author(s):

Sean Chia ◽

Patrick Flagmeier ◽

Johnny Habchi ◽

Veronica Lattanzi ◽

Sara Linse ◽

...

Keyword(s):

Neurodegenerative Disorders ◽

Heterogeneous Nucleation ◽

Amyloid Β ◽

Catalytic Cycle ◽

Amyloid Β Peptide ◽

Complex Interplay ◽

Parkinson’S Diseases ◽

Aβ Aggregation ◽

Aβ Fibrils

The coaggregation of the amyloid-β peptide (Aβ) and α-synuclein is commonly observed in a range of neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases. The complex interplay between Aβ and α-synuclein has led to seemingly contradictory results on whether α-synuclein promotes or inhibits Aβ aggregation. Here, we show how these conflicts can be rationalized and resolved by demonstrating that different structural forms of α-synuclein exert different effects on Aβ aggregation. Our results demonstrate that whereas monomeric α-synuclein blocks the autocatalytic proliferation of Aβ42 (the 42-residue form of Aβ) fibrils, fibrillar α-synuclein catalyses the heterogeneous nucleation of Aβ42 aggregates. It is thus the specific balance between the concentrations of monomeric and fibrillar α-synuclein that determines the outcome of the Aβ42 aggregation reaction.

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Design of Artificial Proteins and Peptides Targeting to Amyloid β Peptide (Aβ) and Control of Aβ Aggregation

Seibutsu Butsuri ◽

10.2142/biophys.47.228 ◽

2007 ◽

Vol 47 (4) ◽

pp. 228-234

Author(s):

Tsuyoshi TAKAHASHI ◽

Sachiko MATSUMURA ◽

Hisakazu MIHARA

Keyword(s):

Amyloid Β ◽

Amyloid Β Peptide ◽

Artificial Proteins ◽

Aβ Aggregation ◽

And Control ◽

Proteins And Peptides

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Endogenous Murine Amyloid-β Peptide Assembles into Aggregates in the Aged C57BL/6J Mouse Suggesting These Animals as a Model to Study Pathogenesis of Amyloid-β Plaque Formation

Journal of Alzheimer s Disease ◽

10.3233/jad-170923 ◽

2018 ◽

Vol 61 (4) ◽

pp. 1425-1450 ◽

Cited By ~ 14

Author(s):

Barbara Ahlemeyer ◽

Sascha Halupczok ◽

Elke Rodenberg-Frank ◽

Klaus-Peter Valerius ◽

Eveline Baumgart-Vogt

Keyword(s):

Amyloid Β ◽

Plaque Formation ◽

Amyloid Β Peptide

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Mechanism of amyloid protein aggregation and the role of inhibitors

Pure and Applied Chemistry ◽

10.1515/pac-2018-1017 ◽

2019 ◽

Vol 91 (2) ◽

pp. 211-229 ◽

Cited By ~ 20

Author(s):

Sara Linse

Keyword(s):

Total Concentration ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Aggregation Process ◽

Secondary Nucleation ◽

Toxic Species ◽

Primary Nucleation ◽

Effective Inhibition ◽

Aβ Aggregation

Abstract Inhibition of amyloid β peptide (Aβ) aggregation is an important goal due to the connection of this process with Alzheimer’s disease. Traditionally, inhibitors were developed with an aim to retard the overall macroscopic aggregation. However, recent advances imply that approaches based on mechanistic insights may be more powerful. In such approaches, the microscopic steps underlying the aggregation process are identified, and it is established which of these step(s) lead to neurotoxicity. Inhibitors are then derived to specifically target steps involved in toxicity. The Aβ aggregation process is composed of at minimum three microscopic steps: primary nucleation of monomers only, secondary nucleation of monomers on fibril surface, and elongation of fibrils by monomer addition. The vast majority of toxic species are generated from the secondary nucleation process: this may be a key process to inhibit in order to limit toxicity. Inhibition of primary nucleation, which delays the emergence of toxic species without affecting their total concentration, may also be effective. Inhibition of elongation may instead increase the toxicity over time. Here we briefly review findings regarding secondary nucleation of Aβ, its dominance over primary nucleation, and attempts to derive inhibitors that specifically target secondary nucleation with an aim to limit toxicity.

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ChemInform Abstract: Therapeutic Approaches Related to Amyloid-β Peptide and Alzheimer′ s Disease

ChemInform ◽

10.1002/chin.199607326 ◽

2010 ◽

Vol 27 (7) ◽

pp. no-no

Author(s):

D. B. SCHENK ◽

R. E. RYDEL ◽

P. MAY ◽

S. LITTLE ◽

J. PANETTA ◽

...

Keyword(s):

Amyloid Β ◽

Amyloid Β Peptide ◽

Therapeutic Approaches

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Dementia-related Bri2 BRICHOS is a versatile molecular chaperone that efficiently inhibits Aβ42 toxicity in Drosophila

Biochemical Journal ◽

10.1042/bcj20160277 ◽

2016 ◽

Vol 473 (20) ◽

pp. 3683-3704 ◽

Cited By ~ 19

Author(s):

Helen Poska ◽

Martin Haslbeck ◽

Firoz Roshan Kurudenkandy ◽

Erik Hermansson ◽

Gefei Chen ◽

...

Keyword(s):

Hippocampal Slices ◽

Amyloid Β ◽

Mushroom Bodies ◽

Amyloid Β Peptide ◽

Specific Expression ◽

Efficient Inhibitor ◽

Transgenic Expression ◽

Aβ Aggregation

Formation of fibrils of the amyloid-β peptide (Aβ) is suggested to play a central role in neurodegeneration in Alzheimer's disease (AD), for which no effective treatment exists. The BRICHOS domain is a part of several disease-related proproteins, the most studied ones being Bri2 associated with familial dementia and prosurfactant protein C (proSP-C) associated with lung amyloid. BRICHOS from proSP-C has been found to be an efficient inhibitor of Aβ aggregation and toxicity, but its lung-specific expression makes it unsuited to target in AD. Bri2 is expressed in the brain, affects processing of Aβ precursor protein, and increased levels of Bri2 are found in AD brain, but the specific role of its BRICHOS domain has not been studied in vivo. Here, we find that transgenic expression of the Bri2 BRICHOS domain in the Drosophila central nervous system (CNS) or eyes efficiently inhibits Aβ42 toxicity. In the presence of Bri2 BRICHOS, Aβ42 is diffusely distributed throughout the mushroom bodies, a brain region involved in learning and memory, whereas Aβ42 expressed alone or together with proSP-C BRICHOS forms punctuate deposits outside the mushroom bodies. Recombinant Bri2 BRICHOS domain efficiently prevents Aβ42-induced reduction in γ-oscillations in hippocampal slices. Finally, Bri2 BRICHOS inhibits several steps in the Aβ42 fibrillation pathway and prevents aggregation of heat-denatured proteins, indicating that it is a more versatile chaperone than proSP-C BRICHOS. These findings suggest that Bri2 BRICHOS can be a physiologically relevant chaperone for Aβ in the CNS and needs to be further investigated for its potential in AD treatment.

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The Neurovascular Unit Dysfunction in Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22042022 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2022 ◽

Cited By ~ 1

Author(s):

Luis O. Soto-Rojas ◽

Mar Pacheco-Herrero ◽

Paola A. Martínez-Gómez ◽

B. Berenice Campa-Córdoba ◽

Ricardo Apátiga-Pérez ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurovascular Unit ◽

Amyloid Β ◽

Brain Parenchyma ◽

Amyloid Angiopathy ◽

Amyloid Β Peptide ◽

Vascular Risk ◽

Therapeutic Approaches ◽

The Brain

Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. Histopathologically, AD presents with two hallmarks: neurofibrillary tangles (NFTs), and aggregates of amyloid β peptide (Aβ) both in the brain parenchyma as neuritic plaques, and around blood vessels as cerebral amyloid angiopathy (CAA). According to the vascular hypothesis of AD, vascular risk factors can result in dysregulation of the neurovascular unit (NVU) and hypoxia. Hypoxia may reduce Aβ clearance from the brain and increase its production, leading to both parenchymal and vascular accumulation of Aβ. An increase in Aβ amplifies neuronal dysfunction, NFT formation, and accelerates neurodegeneration, resulting in dementia. In recent decades, therapeutic approaches have attempted to decrease the levels of abnormal Aβ or tau levels in the AD brain. However, several of these approaches have either been associated with an inappropriate immune response triggering inflammation, or have failed to improve cognition. Here, we review the pathogenesis and potential therapeutic targets associated with dysfunction of the NVU in AD.

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Discovery of Natural Inhibitors of Cholinesterases from Hydrangea: In Vitro and In Silico Approaches

Nutrients ◽

10.3390/nu13010254 ◽

2021 ◽

Vol 13 (1) ◽

pp. 254

Author(s):

Jayeong Hwang ◽

Kumju Youn ◽

Gyutae Lim ◽

Jinhyuk Lee ◽

Dong Hyun Kim ◽

...

Keyword(s):

Senile Plaque ◽

Amyloid Β ◽

Binding Property ◽

Amyloid Β Peptide ◽

New Type ◽

Dual Inhibitors ◽

Rapid Hydrolysis ◽

Hydrolysis Of ◽

Natural Inhibitors

Alzheimer’s disease (AD) is a neurodegenerative disease conceptualized as a clinical-biological neurodegenerative construct where amyloid-beta pathophysiology is supposed to play a role. The loss of cognitive functions is mostly characterized by the rapid hydrolysis of acetylcholine by cholinesterases including acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Moreover, both enzymes are responsible for non-catalytic actions such as interacting with amyloid β peptide (Aβ) which further leads to promote senile plaque formation. In searching for a natural cholinesterase inhibitor, the present study focused on two isocoumarines from hydrangea, thunberginol C (TC) and hydrangenol 8-O-glucoside pentaacetate (HGP). Hydrangea-derived compounds were demonstrated to act as dual inhibitors of both AChE and BChE. Furthermore, the compounds exerted selective and non-competitive mode of inhibition via hydrophobic interaction with peripheral anionic site (PAS) of the enzymes. Overall results demonstrated that these natural hydrangea-derived compounds acted as selective dual inhibitors of AChE and BChE, which provides the possibility of potential source of new type of anti-cholinesterases with non-competitive binding property with PAS.

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